Journal of Neuroscience Research 00:00–00 (2014)

Review Brain Transient Receptor Potential Channels and Stroke Eric Zhang1 and Ping Liao1,2* 1

Calcium Signalling Laboratory, National Neuroscience Institute, Singapore Duke-NUS Graduate Medical School Singapore, Singapore

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Transient receptor potential (TRP) channels have been increasingly implicated in the pathological mechanisms of CNS disorders. TRP expression has been detected in neurons, astrocytes, oligodendrocytes, microglia, and ependymal cells as well as in the cerebral vascular endothelium and smooth muscle. In stroke, TRPC3/4/6, TRPM2/4/7, and TRPV1/3/4 channels have been found to participate in ischemia-induced cell death, whereas other TRP channels, in particular those expressed in nonneuronal cells, have been less well studied. This review summarizes the current knowledge on the expression and functions of the TRP channels in various cell types in the brain and our current understanding of TRP channels in stroke pathophysiology. In an aging society, the occurrence of stroke is expected to increase steadily, and there is an urgent requirement to improve the current stroke management strategy. Therefore, elucidating the roles of TRP channels in stroke could shed light on the development of novel therapeutic strategies and ultimately improve stroke outcome. VC 2014 Wiley Periodicals, Inc. Key words: TRP channels; brain; stroke

Stroke is one of the leading causes of death and disability and occurs when the blood supply to a particular region of the brain is disrupted. There are two types of stroke, ischemic and hemorrhagic. Ischemic stroke is the major form and is caused by the blockage of a cerebral blood vessel when a plaque forms within a blood vessel or an embolus forms elsewhere and travels to the brain. The most efficient management of ischemic stroke is to recanalize the blocked vessel by using the thrombolytic agent tissue plasminogen activator or by using a mechanical device to remove the clot. However, because of a very narrow therapeutic time window, very few patients can benefit from these treatments. The second type of stroke is hemorrhagic stroke, which is caused by the rupture of a cerebral blood vessel. Surgery can effectively stop the bleeding, remove the hematoma, and reduce the intracranial pressure. The past decade has been a period of rapid advances in stroke research. Several different mechanisms have been implicated in ischemia-induced cell death, including C 2014 Wiley Periodicals, Inc. V

excitotoxicity, oxidative stress, inflammation, apoptosis, and necrotic cell death. In this cell-death process, toxic intracellular accumulation of Ca21 plays a prominent role in the damage (Xiong et al., 2013; Chen et al., 2014; Song and Yu, 2014). Past studies have provided a wealth of evidence indicating that glutamate receptors are the major pathway for Ca21 influx in neurons following stroke. Recently, transient receptor potential (TRP) channels have been shown to regulate Ca21 homeostasis and to be involved in stroke pathophysiology. The TRP channel superfamily, first identified in Drosophila, has approximately 30 members that are grouped into six subfamilies on the basis of amino acid sequence homology: TRPA (ankyrin), TRPC (canonical), TRPM (melastatin), TRPML (mucolipin), TRPP (polycystin), and TRPV (vanilloid; Montell, 2005; Wu et al., 2010). There is a seventh TRPN (no mechanopotential) subfamily that exists in worms, Drosophila, and zebrafish but not in mammals (Nilius et al., 2007). TRP channels are widely expressed in numerous mammalian cell types and tissues. They play a critical role in many cellular processes via changing cytosolic free Ca21 concentrations ([Ca21]i). TRP channels regulate [Ca21]i by acting as Ca21-permeable channels in the plasma membrane or via modulating the driving force for Ca21 influx by changing the membrane potential (Nilius et al., 2007). During the past several years, several diseases have been linked to TRP channel malfunctions; therefore, TRP channels are among the most aggressively pursued drug targets (Moran et al., 2011). In stroke, TRP channels have been shown to participate in disease progression. However, among the many TRP channels found in the brain, only a few have been characterized. This review discusses the various TRP channels expressed in different *Correspondence to: Dr. Ping Liao, Calcium Signalling Laboratory, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore 308433. E-mail: [email protected] Received 17 July 2014; Revised 10 September 2014; Accepted 4 November 2014 Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/jnr.23529

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brain regions and cell types and reviews the current understanding of TRP channels in stroke. EXPRESSION AND FUNCTIONS OF TRP CHANNELS IN THE BRAIN The current knowledge on the expression and physiological functions of TRP channels in the brain is summarized in Table I. In Neurons TRPA1 is the only mammalian member of the TRPA family (Nilius et al., 2007) that is expressed in the dorsal root, trigeminal, and nodose ganglia (Story et al., 2003; Brierley et al., 2009; Huang et al., 2012). TRPA1 forms a Ca21- and Zn21-permeable ion channel that senses noxious substances (Wu et al., 2010). Activation of TRPA1 on meningeal nerve endings contributes to various forms of headache, including migraine and environmental irritant-induced headache (Raisinghani et al., 2011; Edelmayer et al., 2012). Additionally, TRPA1 mutation causes familial episodic pain syndrome (Kremeyer et al., 2010). The expression and functions of TRPC channels in neurons have been well characterized. TRPC channels are highly expressed in various regions of the brain. Within the seven members of the TRPC family (TRPC1–7), TRPC1 forms heteromers with TRPC4 or TRPC5 that exhibit distinct properties from homomultimers (Lintschinger et al., 2000; Strubing et al., 2001). Similarly, TRPC3, TRPC6, and TRPC7 coassociate to form heteromers (Goel et al., 2002). In general, TRPC channels are potentiated by the stimulation of G-proteincoupled receptors and receptor tyrosine kinases (Nilius et al., 2007; Wu et al., 2010). TRPC1, TRPC3, and TRPC4 have been implicated in store-operated Ca21 entry (SOCE), and TRPC1 is the most well-established TRPC channel contributing to SOCE. A functional interaction has been identified between TRPC1 and the key SOCE components, stromal interaction molecule (STIM) 1 and Orai1 (Cheng et al., 2013). Functionally, TRPC channels are essential for axon guidance and neurite outgrowth in the developing brain. TRPC1 in neurons regulates glutamate release, growth cone turning, and neurite outgrowth (Narayanan et al., 2008; Gasperini et al., 2009). TRPC2 is a pseudogene in humans, whereas in rodents it is a functional channel in the vomeronasal organ (Liman et al., 1999; Vannier et al., 1999). In vomeronasal sensory neurons, diacyl-glycerol activates TRPC2 (Lucas et al., 2003), suggesting a potential role in pheromone sensing and sexual responses (Leypold et al., 2002; Stowers et al., 2002; Kimchi et al., 2007). TRPC3 channel is widely expressed in the brain and plays an important role in many processes, including brain-derived neurotrophic factor (BDNF)induced axon guidance (Li et al., 2005), neuronal survival (Jia et al., 2007), postsynaptic glutamate transmission (Hartmann et al., 2008, 2011), cerebellar slow excitatory postsynaptic potentials (Hartmann et al., 2008; Nelson

and Glitsch, 2012), and dendritic development of cerebellar Purkinje cells (Becker et al., 2009). TRPC4 and TRPC5 are close homologues. Functionally, inhibition of Ca21 transients in dividing human neuroepithelial cells leads to a significant reduction in proliferation. Therefore, either pharmacological inhibition or shRNA-mediated knockdown of TRPC1 and TRPC4 can greatly reduce neurite extension in postmitotic neurons (Weick et al., 2009). Both TRPC1 and C4 are required for the longlasting depolarization induced by suprathreshold activation of mouse granule cells. They can be activated downstream of N-methyl-D-aspartate (NMDA) receptor activation and can contribute to slow synaptic transmission in the olfactory bulb (Stroh et al., 2012; Tian et al., 2013). TRPC4 has also been suggested to be involved in kisspeptin signaling in female GnRH neurons (Zhang et al., 2013). In the amygdala, TRPC5 is involved in synaptic activation induced by the activation of the group I metabotropic glutamate and cholecystokinin 2 receptors, thereby controlling learned and innate fear-related behaviors (Riccio et al., 2009). Thus, blocking TRPC5 inhibits cholecystokinin-induced neuronal excitability in the entorhinal cortex (Wang et al., 2011). In young hippocampal neurons, TRPC5 modulates neurite extension and growth cone morphology (Greka et al., 2003). TRPC5 is also associated with the depolarized and active state of wake-promoting hypocretin/orexin neurons (Cvetkovic-Lopes et al., 2010). In neuronal progenitor cells, TRPC5 is required for SOCE. As a result, blocking TRPC5 inhibits neuronal differentiation (Shin et al., 2010). Together with TRPC3, TRPC6 contributes to BDNF-induced elevation of [Ca21]i at the growth cones of cerebellar granule cells and is required for BDNFinduced chemoattractive turning (Li et al., 2005). In hippocampal neurons, TRPC6 inhibits NMDA currents (Shen et al., 2013), and its activation modulates dendritic spine morphology induced by hyperforin in CA1 and CA3 pyramidal neurons. TRPC6 is localized to excitatory postsynaptic sites and is critical for the development of dendritic spines and excitatory synapses and, thus, is important for spatial learning and memory. The calcium/ calmodulin-dependent protein kinase type IV-cAMP response element binding protein (CREB)-dependent pathway is associated with the TRPC6 effect on spine formation (Zhou et al., 2008; Heiser et al., 2013). Furthermore, TRPC6 is also required for receptor-activated Ca21 entry in neuronal precursor cells and likely is involved in pluripotent precursor cell differentiation (Cuddon et al., 2008). In dorsal root ganglion neurons, TRPC1 and TRPC6 channels cooperate with TRPV4 channels to mediate mechanical hyperalgesia and primary afferent nociceptor sensitization (Alessandri-Haber et al., 2009). TRPC5 and TRPC6 mediate the muscarinic receptor-induced slow afterdepolarization in cortical pyramidal neurons (Yan et al., 2009). Activation of TRPC3/TRPC7 channels is involved in mGluR1/5mediated glutamatergic excitation of cholinergic Journal of Neuroscience Research

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TABLE I. Expression and Functions of TRP Channels in the Brain Cell type

TRP

Neuron

TRPA1

TRPC1

TRPC2

TRPC3

TRPC4

TRPC5

TRPC6

TRPC7

TRPM2

TRPM3

TRPM4 TRPM5 TRPM7

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Brain region Dorsal root ganglion, nodose ganglia, trigeminal neuron

Functions Pain

References

Story et al., 2003; Brierley et al., 2009; Edelmayer et al., 2012; Huang et al., 2012 Cortex, olfactory bulb, brain Growth cone turning, neurite Strubing et al., 2001; Riccio stem, hippocampus, cerebeloutgrowth, glutamate release et al., 2002; Cristino et al., lum, substantia nigra, basal 2006; Kunert-Keil et al., ganglia 2006; Martorana et al., 2006; Chung et al., 2007; Meis et al., 2007; Narayanan et al., 2008; Gasperini et al., 2009; Weick et al., 2009 Rodent vomeronasal organ Pheromone sensing, sexual Liman et al., 1999; Vannier response et al., 1999; Leypold et al., 2002; Stowers et al., 2002; Lucas et al., 2003; Kimchi et al., 2007 Cortex, cerebellum, hippocam- Axon guidance, neuronal sur- Li et al., 2005; Chung et al., 2007; Jia et al., 2007; Hartpus, brainstem, striatum vival, glutamate transmission, EPSP, dendrite developmann et al., 2008, 2011; Becker et al., 2009; Nelson ment, respiratory rhythm and Glitsch, 2012 Lateral septum, hippocampus, Neurite extension, synaptic Riccio et al., 2002; Chung cortex, olfactory bulb, amygtransmission, pituitary et al., 2007; Huang et al., dala, basal ganglia, neonatal gonadotropins secretion 2007; Meis et al., 2007; cerebellum Wang et al., 2007; Weick et al., 2009; Stroh et al., 2012; Tian et al., 2013; Zhang et al., 2013 Hippocampus, amygdala, audi- Synaptic activation, fear, neu- Strubing et al., 2001; Greka tory cortex, somatosensory rite extension, growth cone et al., 2003; Chung et al., cortex, basal ganglia morphology 2007; Meis et al., 2007; M. Wang et al., 2007; Riccio et al., 2009; Yan et al., 2009; S. Wang et al., 2011 Dentate gyrus, cerebellum, Neuronal survival, spatial Li et al., 2005; Chung et al., hippocampus, cortex learning and memory, neu2007; Huang et al., 2007; Jia rite outgrowth et al., 2007; Zhou et al., 2008; Yan et al., 2009; Gibon et al., 2010; Heiser et al., 2013; Nagy et al., 2013; Shen et al., 2013 Substantia nigra, basal ganglia, Excitation of cholinergic inter- Berg et al., 2007; Chung et al., brainstem neurons, respiratory rhythm 2007; Ben-Mabrouk and Tryba, 2010 Cerebrum, cerebellum, foreROS sensitive Kaneko et al., 2006; Yamabrain, hippocampus moto et al., 2007; Olah et al., 2009; Bai and Lipski, 2010; Kozai et al., 2013 Glutamate release Nealen et al., 2003; Developing cerebellar cortex, trigeminal neurons Zamudio-Bulcock and Valenzuela, 2011; ZamudioBulcock et al., 2011 Whole brain Burst firing, inspiratory burst Launay et al., 2002; Mironov, 2008; Mrejeru et al., 2011 Olfactory bulb, pituitary Sense putative semiochemicals Fonfria et al., 2006b; Lin et al., 2007; Oshimoto et al., 2013 Cortex, hippocampus

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TABLE I. Continued Cell type

TRP

Brain region

Functions

References

Oxidative stress, dopaminergic neuron development

TRPM8

TRPML3

TRPV1

TRPV2

TRPV3

TRPV4

Astrocyte

TRPA1 TRPC1–5

TRPC6 TRPM3 TRPV1

TRPV2 TRPV4

Microglia

TRPC1–6 TRPM2

TRPM4 TRPM7 TRPV1

Oligodendrocyte

TRPV4 TRPM3 TRPC3

Aarts et al., 2003; Lipski et al., 2006; Sun et al., 2009; Decker et al., 2013 Sensory neurons, hippocampus, Thermoreceptor Voets et al., 2007; Crawford mesencephalon et al., 2009; Du et al., 2009; Bharate and Bharate, 2012 Cochlear hair cell Hearing Atiba-Davies and NobenTrauth, 2007; Wu et al., 2010 Whole brain Pain, body temperature Mezey et al., 2000; Iida et al., control, anxiety, fear, LTP, 2005; Toth et al., 2005; LTD Cristino et al., 2006; Marsch et al., 2007; Maione et al., 2009; Micale et al., 2009; Pan et al., 2011; Huang et al., 2012; Brown et al., 2013 Hypothalamus, hindbrain, Axonal outgrowth, memory Wainwright et al., 2004; Shicerebellum, striatum, basaki et al., 2010; Pan hippocampus, hypothalamus et al., 2011; Nedungadi et al., 2012; Shibasaki et al., 2013 Hippocampus Synaptic plasticity, emotional Lipski et al., 2006; Moussaieff response et al., 2008; Brown et al., 2013 Hypothalamus, cortex, hippo- Osmosis, affect neuronal Liedtke et al., 2000; Guatteo campus, cerebellum, substanexcitability et al., 2005; Shibasaki et al., tia nigra 2007; Kauer and Gibson, 2009 Hippocampus, striatum Regulate inhibitory synapse Shigetomi et al., 2012 Adult cortex SOCE, mechanical stimulation, Pizzo et al., 2001; Grimaldi glutamate release et al., 2003; Golovina, 2005; Malarkey et al., 2008; Shirakawa et al., 2010; Akita and Okada, 2011 Embryonic cortex (TRPC6) ROCE Beskina et al., 2007 Cerebellar Bergman glia Cerebellar development? Zamudio-Bulcock et al., 2011 Circumventricular organs, Possibly sense blood-borne Toth et al., 2005; Cristino astrocytes surrounding small stimuli et al., 2006; Mannari et al., vessels 2013 Cerebellum Lipid metabolism? Shibasaki et al., 2013 Cortex, hippocampus Osmotic sensing, vasodilation Benfenati et al., 2007, 2011; Butenko et al., 2012; Dunn et al., 2013 Whole brain Ohana et al., 2009 Kraft et al., 2004; Fonfria Cerebral cortex, thalamus, H2O2 and ADPR- induced et al., 2006a; Ohana et al., Ca21 influx, pain hippocampus, midbrain, 2009; Haraguchi et al., cerebellum 2012; Isami et al., 2013 Beck et al., 2008 Cultured microglia Ca21-activated Cultured microglia Spontaneously activated Jiang et al., 2003 Substantia nigra, cultured Mitochondrial damage and Kim et al., 2006; Schilling and microglia cytochrome c release, ROS Eder, 2009, 2010; Park production et al., 2012; Talbot et al., 2012 Striatum, cultured microglia LPS-induced activation Konno et al., 2012 Hoffmann et al., 2010 White matter Sphingosine-induced Ca21 entry Cortex, thalamus, globus Unknown Fusco et al., 2004 pallidus, substantia nigra, cerebellar cortex, striatum

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Brain TRP Channels and Stroke TABLE I. Continued Cell type Ependymal cell

TRP TRPA1, TRPV1, TRPV3

Endothelium

Smooth muscle

Brain region Embryonic choroid plexus

TRPA1

Cerebral and cerebellar arteries

TRPM4 TRPV3

Cerebral and spinal cord capillary Cerebral arteries

TRPV4 TRPM4

Middle cerebral artery Cerebral and cerebellar artery

TRPV4

Cerebral artery

interneurons in the basal ganglia (Berg et al., 2007). It is noteworthy that the same two channels in the brainstem can be activated by substance P and can modulate respiratory rhythm (Ben-Mabrouk and Tryba, 2010). The TRPM2 channel is a Ca21-permeable channel expressed in various regions of the brain. It is activated by intracellular adenosine diphosphoribose (ADPR), hydrogen peroxide, heat, and reactive oxygen species (ROS; Nilius et al., 2007; Wu et al., 2010). Abundantly expressed in neonatal cerebellar Purkinje cells, the steroid-sensitive TRPM3 channel is required for pregnenolone sulfate-induced glutamate release (Zamudio-Bulcock and Valenzuela, 2011; Zamudio-Bulcock et al., 2011). TRPM4 and TRPM5 channels are the only two members of the TRP superfamily that are Ca21-impermeable monovalent channels (Nilius et al., 2007). TRPM4 is regulated by intracellular Ca21 and ATP levels (Vennekens and Nilius, 2007). Found in primary cultured hippocampal neurons and the distal cerebrospinal fluid-contacting neurons of the mesencephalon (Crawford et al., 2009; Du et al., 2009), TRPM4 likely controls the neuronal membrane potential. Therefore, it is involved in tonic and bursting activity in dopamine neurons (Mrejeru et al., 2011) and the generation of inspiratory rhythmic bursts in the inspiratory neurons within the lower brainstem (Mironov, 2008). TRPM5 is expressed in the pituitary and olfactory bulbs (Fonfria et al., 2006b; Lin et al., 2007). The function of TRPM5 in the olfactory bulbs relates to sensing semiochemicals (Lin et al., 2007; Oshimoto et al., 2013). TRPM7 in neurons plays a key role in anoxic neuronal death (Aarts et al., 2003; Lipski et al., 2006; Sun et al., 2009). In sympathetic neurons, the vesicular TRPM7 channel is required for release of the positively charged neurotransmitter acetylcholine (Krapivinsky et al., 2006). In zebrafish, TRPM7 participates in the differentiation and function of dopaminergic neurons during development (Decker et al., 2013). TRPM8 in sensory neurons has been studied extensively. It detects cold temJournal of Neuroscience Research

Functions Possibly regulate CSF ionic composition and osmolarity during development Endothelium dependent vasodilation Vascular damage following injury Endothelium-dependent vasodilation PLA2 induced vasodilation Pressure-induced vasoconstriction

Vasodilation

5

References Jo et al., 2013

Earley et al., 2009; Qian et al., 2013 Gerzanich et al., 2009; Loh et al., 2013 Earley et al., 2010 MarrelLi et al., 2007 Earley et al., 2004; Reading and Brayden, 2007; Crnich et al., 2010; Gonzales et al., 2010; Gonzales and Earley, 2012 Earley et al., 2005

perature and is sensitive to cooling compounds, such as menthol and icilin (Voets et al., 2007; Bharate and Bharate, 2012). The function of TRPML channels in neurons is not completely known. Their expression was found primarily in hair cells of the cochlea. The gain-of-function mutation of TRPML3 causes the varitint waddler phenotype that includes hearing loss and pigmentation defects in the skin (Atiba-Davies and Noben-Trauth, 2007; Wu et al., 2010). TRPV1 expression has been reported for neurons throughout the brain (Mezey et al., 2000). However, it was revealed that, in TRPV1 reporter mice, TRPV1 is restricted primarily to nociceptors in primary sensory ganglia, with minimal expression in a few discrete brain regions, most notably in a contiguous band of cells within and adjacent to the caudal hypothalamus (Cavanaugh et al., 2011). TRPV1 is known as the capsaicin receptor and has been suggested to control body temperature (Iida et al., 2005). Thus, blocking TRPV1 receptors can reduce anxiety-like behaviors, fear conditioning, and stress sensitization in mice, which is mirrored by a decrease in hippocampal long-term potentiation (LTP; Marsch et al., 2007; Gibson et al., 2008; Micale et al., 2009). TRPV1 also controls long-term depression (LTD) in the rodent superior colliculus (Maione et al., 2009). In developing sensory and motor neurons, TRPV2 regulates axon outgrowth after activation by membrane stretch (Shibasaki et al., 2010). Both TRPV1 and TRPV2 are involved in the x-3 polyunsaturated fatty acid docosahexaenoic acid-induced cognitive enhancement (Pan et al., 2011). TRPV3 is a Ca21-permeable temperaturesensitive channel (Smith et al., 2002; Xu et al., 2002). TRPV3 knockout mice exhibit reduced LTP and LTD, suggesting a role in synaptic plasticity (Brown et al., 2013). Activation of TRPV3 in the brain by incensole acetate causes anxiolytic-like and antidepressant-like behavioral effects in mice (Moussaieff et al., 2008). Single

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nucleotide polymorphisms in TRPV1 (rs222741) and TRPV3 (rs7217270) were also found to be associated with migraines (Carreno et al., 2012). TRPV4 was first cloned from neurons and found to be sensitive to osmotic pressure (Liedtke et al., 2000). Thus, it is required for hypotonic stimulus-induced nociception and chemotherapy-induced neuropathic pain (AlessandriHaber et al., 2003, 2004). TRPV4 gain-of-function mutations cause cytotoxic hypercalcemia in axonal Charcot-Marie-Tooth neuropathies, affecting both motor and sensory nerves (Fecto et al., 2011; Klein et al., 2011; Jang et al., 2012). The behavioral responses to thermal stimulation in TRPV4 knockout mice remain controversial (Wu et al., 2010). Furthermore, TRPV3 and TRPV4 in nigral dopaminergic neurons are constitutively active at near-physiological temperatures, affecting the excitability and calcium homeostasis of these neurons (Guatteo et al., 2005). In Astrocytes Compared with neurons, fewer TRP channels are expressed in astrocytes, and most of their functions remain unknown. Spontaneous openings of TRPA1 (the only mammalian TRPA family member) in astrocytes regulate interneuron inhibitory synapse efficacy by reducing GABA transport by GAT-3 (Shigetomi et al., 2012). It is well known that SOCE is important for Ca21 signaling in nonexcitable cells (Putney, 1990). In contrast to microglia, in which SOCE is mediated by Orai and Stim1 (Kettenmann et al., 2011), TRPC channels play a critical role in SOCE in astrocytes. All TRPC channels (TRPC1–6) are expressed in cultured embryonic astrocytes (Pizzo et al., 2001; Grimaldi et al., 2003). TRPC1 and TRPC3 likely contribute to SOCE, induced by endoplasmic reticulum (ER) depletion or metabotropic stimulation (Golovina, 2005; Malarkey et al., 2008; Shirakawa et al., 2010; Akita and Okada, 2011). TRPC6 is involved in receptoroperated Ca21 entry (ROCE) in cultured embryonic cortical astrocytes (Beskina et al., 2007). Therefore, interleukin-1b-induced Ca21 entry has been shown to be disrupted by TRPC6 knockdown. The TRPM3 channel was found in cerebellar Bergman glia during development (Zamudio-Bulcock et al., 2011). Its functions have yet to be identified. TRPV1 was detected in astrocytes in circumventricular organs. Injection of the selective agonist resiniferatoxin triggers the expression of the immediate early gene c-Fos (Mannari et al., 2013). Cerebellar astrocytes express the TRPV2 channel, which is activated by very high temperature (>50 C), and may regulate neuronal activity in response to lipid metabolism (Shibasaki et al., 2013). TRPV4 was found in astrocytes within the cortex and hippocampus. It is involved in osmotic sensing and regulates cell volume together with aquaporins (Benfenati et al., 2007, 2011; Butenko et al., 2012). In the endfeet that encase blood vessels, TRPV4-mediated Ca21 influx responds to neuronal activation and thereafter enhances vasodilation (Dunn et al., 2013).

In Oligodendrocytes Until recently, only TRPC3 and TRPM3 had been found in oligodendrocytes. TRPM3 is located on oligodendrocytes in the white matter of the brain after the onset of myelination and governs sphingosine-induced Ca21 entry (Hoffmann et al., 2010). TRPC3 was found in the grey matter of the brain (Fusco et al., 2004). The functions of TRPC3 in oligodendrocytes remain largely unknown. In Microglia RT-PCR results from cultured rat microglia reveal the following rank order of mRNA expression: TRPM7 > TRPC6 > TRPM2 > TRPC1 > TRPC3  TRPC4 > TRPC7 > TRPC5 > TRPC2 (Ohana et al., 2009). In addition to neuronal expression, microglial TRPM2 has been found in various regions of the brain. TRPM2 is activated by intracellular ADPR or extracellular H2O2 and governs Ca21 entry to microglial cells (Fonfria et al., 2006a; Kraft et al., 2004). After spinal cord injury, microglial activation is suppressed in TRPM2 knockout mice (Haraguchi et al., 2012; Isami et al., 2013). A Ca21-activated TRPM4-like current has been identified in nonactivated cultured mouse microglial cells (Beck et al., 2008), but TRPM4 expression and function require further study. In cultured rat microglia, TRPM7 is activated spontaneously after break in, and its activities are inhibited by elevated intracellular Mg21 but are not affected by cell swelling or a change in [Ca21]i (Jiang et al., 2003). TRPV1 is expressed in rat and human microglial cells. Injection of TRPV1 agonists into the substantia nigra of the rat brain causes microglial cell death via Ca21-mediated mitochondrial damage and cytochrome c release. Therefore, inhibition of TRPV1 abolishes ROS production after lysophosphatidylcholine stimulation (Kim et al., 2006; Schilling and Eder, 2009, 2010). Opening TRPV1 by capsaicin contributes to mesencephalic dopaminergic neuronal survival by inhibiting microglial activation-mediated oxidative stress (Park et al., 2012) and induces functional kinin B1 receptors in the rat spinal cord (Talbot et al., 2012). In cultured microglia, lipopolysaccharide (LPS) treatment releases tumor necrosis factor (TNF)-a and increases the expression of galectin-3, both of which are suppressed by TRPV4 agonists, suggesting a role for TRPV4 in microglial activation. Therefore, in mice receiving a ventricular LPS injection, microglial activation can be inhibited by concurrent administration of TRPV4 agonists (Konno et al., 2012). In Ependymal Cells The embryonic choroid plexus expresses TRPA1, TRPV1, and TRPV3 channels. Their expression declines progressively after day 19 of gestation, suggesting that they may regulate composition changes of the cerebral spinal fluid during development (Jo et al., 2013). Journal of Neuroscience Research

Brain TRP Channels and Stroke

In the Cerebral Vascular Endothelium Many TRP channels have been found in the vascular endothelium from various regions. These TRP channels modulate cytosolic [Ca21]i and regulate membrane potential. Therefore, they are involved in a number of physiological and pathophysiological processes, including vascular contraction, endothelial barrier integrity, oxidative damage, and perturbed angiogenic competence (Kwan et al., 2007). Under physiological conditions, only a few TRP channels, such as TRPA1, TRPV3, and TRPV4, have been found in the cerebral vascular endothelium and are associated with endothelium-dependent artery dilation/constriction (Earley, 2011). Endothelial TRPA1 in cerebral arteries mediates vasodilation by a mechanism requiring Ca21activated K1 channels and inward rectifying K1 channels in myocytes (Earley et al., 2009). TRPV3 is also present in native cerebral artery endothelial cells. Carvacrol can hyperpolarize the smooth muscle membrane potential and elicit vasodilation by activating endothelial TRPV3 (Earley et al., 2010). In the middle cerebral artery, the purinergic receptor agonist UTP increases endothelial [Ca21]i via TRPV4 channels, a process requiring phospholipase A2 (PLA2)-mediated liberation of arachidonic acid (AA) from plasma membrane and conversion to epoxyeicosatrienoic acids by CYP epoxygenase. Blocking TRPV4 reduces endothelial [Ca21]i and thus inhibits vasodilation (Marrelli et al., 2007). Under pathological conditions, the TRPM4 channel is upregulated in the cerebral and spinal cord vascular endothelium and causes oncotic cell death following ischemic injury (Gerzanich et al., 2009; Loh et al., 2013). In the Smooth Muscle of Cerebral Blood Vessels Several TRP channels have been found to play functional roles in the vascular smooth muscle (Di and Malik, 2010). In cerebral blood vessels, only TRPM4 and TRPV4 channels have been well studied. TRPM4 is required for pressure-induced smooth muscle cell depolarization and subsequent vasoconstriction (Earley et al., 2004). Therefore, TRPM4 is critical for the autoregulation of cerebral blood flow (Reading and Brayden, 2007). TRPV4 is expressed in both the cerebral smooth muscle and the endothelium. In smooth muscle cells, TRPV4 couples with the ryanodine receptor and the largeconductance Ca21-activated K1 channel, eliciting hyperpolarization upon activation. Cerebral arterial dilation was observed in response to 11,12-epoxyeicosatrienoic acid, a TRPV4 activator (Earley et al., 2005). TRP CHANNELS AND STROKE Among the numerous TRP channels expressed in the brain, only a few have been shown to be involved in stroke pathophysiology. Their expression and roles are summarized in Table II. Journal of Neuroscience Research

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TRPC3/4 and Stroke TRPC3 is involved in astrogliosis after stroke. In cultured rat and human astrocytes, thrombin treatment activated gliosis and upregulated TRPC3 expression through protease-activated receptor 1, extracellular signal-regulated protein kinase (ERK), c-JunNH2-terminal kinase, and nuclear factor-jB signaling (Nakao et al., 2008; Shirakawa et al., 2010). Thrombin is a major blood-derived serine protease. After stroke, thrombin leaks into the brain parenchyma upon blood–brain barrier (BBB) disruption and worsens brain injury by activating astrocytes (Nishino et al., 1993). Functionally, upregulated TRPC3 protein is associated with increased Ca21 influx in astrocytes and regulates gliosis following thrombin treatment (Shirakawa et al., 2010). In vivo experiments using an intracerebral hemorrhage model demonstrated that blocking TRPC3 with a specific blocker, ethyl-1-(4-(2,3,3-trichloroacrylamide)phenyl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylate (Pyr3) improves functional outcomes and attenuates astrogliosis (Munakata et al., 2013). Because TRPC3 is expressed in multiple cell types, including neuron, immune cell, and endothelium (Eder et al., 2007), the beneficial effect of Pyr3 may be attributed to other cells as well as astrocytes. This is supported by a study showing that overexpression of TRPC3 increases apoptosis in rodent hearts following ischemia–reperfusion (Shan et al., 2008). Thus, the therapeutic prospect of blocking TRPC3 in stroke requires further study to examine the effects on other cells. TRPC4 expression was found to be higher in neurons in the striatum and hippocampus after focal ischemic stroke. Because the upregulation persisted from 12 hr to 3 days after operation, it has been suggested that TRPC4 plays a role in both acute and delayed neuronal injury (Gao et al., 2004). However, the role of TRPC4 after stroke remains largely unknown. TRPC6 and Stroke Disruption of TRPC6 function is detrimental to neuronal survival after stroke. In a transient middle cerebral artery occlusion (tMCAO) model, the TRPC6 mRNA level remained unchanged after reperfusion (Du et al., 2010), whereas the protein level decreased (Du et al., 2010; Lin et al., 2013a,b) as a result of calpainmediated proteolysis (Du et al., 2010). In addition, neuronal downregulation of TRPC6 was also found in animals with pilocarpine-induced status epilepticus (Kim et al., 2013). Calpains are Ca21-dependent nonlysosomal cysteine proteases. Under ischemic conditions, excessive Ca21 influx through NMDA receptors in neurons initiates calpain activation (Goll et al., 2003). Therefore, TRPC6 degradation after stroke is calcium dependent. We reviewed the important roles of TRPC6 in neuronal function above. Maintaining proper TRPC6 protein level is critical for poststroke neuroprotection through the CREB signaling pathway (Du et al., 2010). Blocking

2-APB, Gd and La , SKF96365, ruthenium red, pyrazole derivative Pyr3 Gd31 and La31, ML204, fenamates Gd31 and La31, Clotrimazole, 2APB, GsMTx-4, SKF-96365, gestagen norgestimate, compound 8009-5364 Gd31 and La31, fenamates, clotrimazole and econazole Spermine, flufenamic acid, quinine, quinidine, ATP, ADP, AMP, 9-phenanthrol, glibenclamide SKF-96365, 2-APB, waixenicin A, NS8593, nafamostat mesylate, sphingosine capsaicin, Ruthenium red, A425619, IBTU, SB-366791, and AMG 9810 Gd31 and La31, Citral, ruthenium red, HC-067047, RN-1747 and RN-1734, Butamben GSK2193874

31

Blockers

31

Transient global ischemia (Butenko et al., 2012)

" (Butenko et al., 2012)

" (Aarts et al., 2003)

" (Jiang et al., 2008)

tMCAO, global ischemia (Jiang et al., 2008; Sun et al., 2009) tMCAO

" (Butenko et al., 2012)

" (Loh et al., 2013)

" (Loh et al., 2013)

pMCAO (Loh et al., 2013)

unknown

" (Fonfria et al., 2006a)

" (Fonfria et al., 2006a)

unknown

# (Du et al., 2010; Lin et al., 2013a,b)

# (Du et al., 2010; Lin et al., 2013a,b)

tMCAO† (Du et al., 2010; Lin et al., 2013a,b)

tMCAO (Fonfria et al., 2006a)

unknown

" (Gao et al., 2004)

pMCAO* (Gao et al., 2004)

Activity after stroke " (Shirakawa et al., 2010)

Expression after stroke " (Shirakawa et al., 2010)

Stroke model Hemorrhage stroke (Munakata et al., 2013)

*pMCAO, permanent middle cerebral artery occlusion. † tMCAO, transient middle cerebral artery occlusion.

TRPV4

TRPV1

TRPM7

TRPM4

TRPM2

TRPC6

TRPC4

TRPC3

TRP channels

TABLE II. Expression and Functions of TRP Channels After Stroke

Thermoregulation (Muzzi et al., 2012; Cao et al., 2014) Astrogliosis (Butenko et al., 2012), neuronal excitotoxicity (Li et al., 2013)

Neuronal death (Sun et al., 2009)

Controversial (Isaev et al., 2002; Bai and Lipski, 2010) Angiogenesis (Loh et al., 2013)

Neuronal survival (Du et al., 2010; Lin et al., 2013a,b)

Unknown

Astrogliosis (Munakata et al., 2013)

Role in stroke

8 Zhang and Liao

Journal of Neuroscience Research

Brain TRP Channels and Stroke

TRPC6 degradation may help to promote CREB phosphorylation and thereby enhance the expression of downstream neuroprotective molecules such as BDNF and Bcl-2 (Kitagawa, 2007). The beneficial role of TRPC6 after stroke is supported by a study of hyperforin, a lipophilic constituent of the medicinal herb St. John’s wort (Lin et al., 2013b), and resveratrol, a polyphenol found in grapes, berries, and peanuts (Lin et al., 2013a). By using rodent tMCAO models, two studies revealed that resveratrol or hyperforin elevates TRPC6 expression and CREB phosphorylation. As a result, the infarct volume was reduced, accompanied by enhanced neurological function. It is of interest that the overexpression or the downregulation of TRPC6 can suppress or aggravate, respectively, the Ca21 overload induced by NMDA (Li et al., 2012). The mechanisms involve the phosphorylation of NMDA receptors by increased activities of ERK (Jia et al., 2007), calcineurin (Liu and Ji, 2012), and CaMK (Tai et al., 2008) via Ca21 influx through TRPC6 channels. Excitotoxicity caused by the activation of NMDA receptors has been studied extensively in stroke because the Ca21 overload contributes to cell death following ischemia. However, numerous attempts to block NMDA receptors directly have failed to improve stroke outcome because of severe side effects for healthy neurons that require NMDA receptors for normal function (Yu et al., 2013). Thus, targeting TRPC6 is an ideal way to regulate NMDA receptors in the hypoxic region because TRPC6 truncation occurs only in ischemic brain tissue, and inhibiting TRPC6 degradation will have a minimal effect on healthy neurons. TRPM2 and Stroke TRPM2 is activated by intracellular ADPR, hydrogen peroxide, heat, and ROS (Nilius et al., 2007; Wu et al., 2010), which are linked to cell death. In a tMCAO model, TRPM2 mRNA was found to be upregulated in the chronic stage from 1 to 4 weeks postoperation (Fonfria et al., 2006a). Because TRPM2-like currents have been identified in microglial cells, it has been suggested that TRPM2 activation plays a role in stress-induced activation of microglia and in downstream pathological processes. However, hippocampal and cortical neurons also express TRPM2 (Kaneko et al., 2006; Olah et al., 2009; Bai and Lipski, 2010), which is responsible for H2O2induced Ca21 entry and subsequent neuronal death (Kaneko et al., 2006). Therefore, targeting TRPM2 for potential stroke therapy requires a balance between effects on microglia and neurons. Indeed, pretreatment with clotrimazole, a nonselective TRPM2 blocker, reduces the death of cultured rat cerebellar granule cells following oxygen glucose deprivation and the excitotoxic effect of glutamate on cultured hippocampal neurons and cerebellar granule cells (Isaev et al., 2002). However, in a separate study carried out by Bai and Lipski (2010), blockers of TRPM2 channels, clotrimazole, N-(p-amylcinnomoyl) anthranilic acid, or flufenamic acid, failed to protect pyramidal neurons from exogenous H2O2-induced cell Journal of Neuroscience Research

9

death. Because the therapeutic potential of blocking TRPM2 in stroke remains controversial, a TRPM2specific blocker or a study of TRPM2 knockout mice is required to verify whether inhibiting TRPM2 is ultimately beneficial to stroke outcome. TRPM4 and Stroke TRPM4 has been proposed to form the pore of the SUR1/TRPM4 channel together with SUR1 (Kurland et al., 2013). SUR1 is a known subunit of KATP channels, which play an important role in pancreatic b cells (Seino, 1999). Antagonists to SUR1, such as sulphonylureas, have been widely used to treat diabetic patients to promote insulin secretion. In the central nervous system (CNS), SUR1 is expressed in some neurons but not in astrocytes or capillaries. After injury, SUR1 is upregulated in many CNS disorders, including stroke, traumatic brain injury, subarachnoid hemorrhage, and spinal cord injury (SCI; Simard et al., 2010a). In animal models and human stroke tissues, upregulation of SUR1 has been found in neurons, astrocytes, and endothelium (Simard et al., 2006, 2010b; Mehta et al., 2013). TRPM4 is a monovalent nonselective cation channel. It is activated by ATP depletion and increases in [Ca21]i (Vennekens and Nilius, 2007). After ischemia, opening of the SUR1/TRPM4 channel is supposed to cause oncotic cell death as a result of unchecked Na1 influx (Simard et al., 2012). Therefore, blocking SUR1 with sulfonylureas was found to improve stroke outcome (Simard et al., 2013). Recently, our group reported an upregulation of TRPM4 in the vascular endothelium following stroke (Loh et al., 2013). When TRPM4 was inhibited by siRNA. angiogenesis was promoted, resulting in a reduction of infarction and an enhancement of motor functions. The capillary fragmentation seen in control animals disappeared in animals receiving TRPM4 siRNA treatment, similar to the findings from SCI studies in which TRPM4 was inhibited (Gerzanich et al., 2009). In SCI, de novo expression of TRPM4 was shown to cause capillary fragmentation, and in vivo suppression with TRPM4 antisense or knockout of the TRPM4 gene helped to preserve vascular integrity and prevent secondary hemorrhage. Although increasing evidence supports the notion that TRPM4 is a target for stroke therapy, the underlying mechanisms are not fully understood. For example, TRPM4 has also been found in vascular smooth muscle (Earley, 2013) and immune cells (Vennekens et al., 2007; Barbet et al., 2008). Therefore, the potential adverse effects of TRPM4 blockade require further investigation. However, because TRPM4 generally is not highly expressed in the brain and TRPM4 knockout mice are viable (Vennekens et al., 2007), the expected side effects of targeting TRPM4 in stroke may be minimal. TRPM7 and Stroke TRPM7 is a ubiquitously expressed nonselective cation channel that possesses protein kinase activities (Wu et al., 2010). At negative membrane potentials, TRPM7

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conducts a small inward current by transporting exclusively divalent cations, such as Ca21 and Mg21, down their concentration gradients. At positive membrane potentials, TRPM7 conducts an outward rectifying current resulting from removal of the voltage-dependent block by extracellular divalent cations (Nadler et al., 2001; Penner and Fleig, 2007). The inward current is strongly potentiated by a decrease in extracellular pH (Jiang et al., 2005; Li et al., 2007). The role of TRPM7 in stroke has been extensively studied. After ischemia/hypoxia, TRPM7 activity is greatly enhanced (Aarts et al., 2003), possibly from both an upregulation of the channel protein (Jiang et al., 2008) and channel potentiation resulting from an acidic environment caused by stroke. Excessive influx of the most permeable metal ions, Ca21, Mg21, and Zn21, through TRPM7 is highly toxic to cells (Lee et al., 2002; Inoue et al., 2010). In addition to metal ion overloading, TRPM7 contributes to ROS production in neurons following hypoxia (Aarts et al., 2003). The function and expression of TRPM7 are regulated by nerve growth factor via the phosphoinositide 3-kinase signaling pathway (Tian et al., 2007; Jiang et al., 2008). In a recent study, the mixed-lineage kinase domain-like protein (MLKL) was reported to be essential for TNF-induced necroptosis. TRPM7 is an MLKL downstream target to mediate Ca21 entry and is therefore involved in TNF-induced necroptosis (Cai et al., 2014). Furthermore, suppression of TRPM7 diminishes neuronal death and prevents ischemia-induced deficits in LTP and fear-associated or spatial–navigational memory (Sun et al., 2009). TRPM7 expression was found to be upregulated in the heart following ischemia reperfusion (Demir et al., 2014), suggesting that TRPM7 might also play a role in ischemic damage outside the brain. It is noteworthy that knock down of TRPM7 did not lead to substantial alterations in the electrophysiological properties of hippocampal neurons (Sun et al., 2009), indicating that the side effects of inhibiting TRPM7 in healthy neurons in the CNS may be minimal after stroke. However, the potential side effects outside the brain have not been examined. TRPM7 is essential for embryonic development, and deletion of TRPM7 is lethal during embryogenesis in mice (Jin et al., 2008). Krapivinsky et al. (2006) showed that TRPM7 is important in cholinergic neurotransmission. Therefore, TRPM7 blockade may affect synaptic transmission. Moreover, TRPM7 was found in the endothelium (Inoue and Xiong, 2009), vascular smooth muscle (He et al., 2005), gastrointestinal tract interstitial pacemaker cells (Kim et al., 2005), human epithelial cells (Numata et al., 2007), and immune cells (Jin et al., 2008). Thus, potential adverse effects may occur within these tissues and organs when TRPM7 is blocked. TRPV1 and Stroke Hypothermia is a powerful neuroprotective strategy for managing acute brain injuries such as stroke (Diller

and Zhu, 2009; Yenari and Hemmen, 2010). However, current protocols for hypothermia trigger adverse complications, such as cold defense mechanisms, which reduce their effectiveness and preclude their broad application (Krieger et al., 2001; De Georgia et al., 2004; Nakamura and Morrison, 2011; Zgavc et al., 2011). Opening TRPV1 by capsaicin is presumed to promote hypothermia via activation of the channel in the brain and/or peripheral nerves (Miller et al., 1982; Romanovsky, 2007; Fosgerau et al., 2010). The drop in body temperature is a result of hypothalamus-driven autonomic responses to enhance heat loss (Caterina et al., 2000; Caterina, 2007). As such, selective targeting of thermosensitive TRPV1 can produce hypothermia without significant adverse effects (Cao et al., 2014). In a rodent tMCAO model, pharmacologically activating TRPV1, immediately after reperfusion successfully induced reversible hypothermia and yielded neuroprotection before the infarction had fully developed (Cao et al., 2014). Such neuroprotection is believed to be due to hypothermia and not to either the central or the peripheral effects of TRPV1 activation (Muzzi et al., 2012). In addition to acute stroke management, long-term activation of TRPV1 may help reduce stroke risk. In a study by Xu et al. (2011), chronic dietary capsaicin significantly relaxed basilar arteries, reduced intracranial arterial hypertrophy, and was associated with eNOS phosphorylation in stroke-prone, spontaneously hypertensive rats. Thereafter, stroke occurrence was delayed and accompanied by increased survival time. In neonatal rats, capsaicin pretreatment yielded neuroprotection against hypoxia/ ischemia-induced brain damage (Khatibi et al., 2011). Furthermore, the therapeutic effect of capsaicin has been shown in ischemic injury in other tissues, including heart, kidney, and lung. The mechanism likely involves the inhibition of inflammation and oxidative stress induced by hypoxia/ischemia (Rayamajhi et al., 2009; Wang et al., 2012; Robbins et al., 2013). Of particular importance, BBB permeability can be increased by peripheral nerve injury or by application of capsaicin directly to the brain surface or to the peripheral sciatic nerve (Hu et al., 2005; Beggs et al., 2010), indicating a damaging role of TRPV1 activation on BBB integrity. Accordingly, blocking TRPV1 with capsazepine protected parenchymal BBB after hemorrhagic shock or ischemia–reperfusion (Akabori et al., 2007; Gauden et al., 2007). Therefore, the risk of hemorrhage may be elevated when TRPV1 agonists are applied after ischemic stroke. In this regard, the potential side effects of either blocking or activating TRPV1 for stroke therapy require careful investigation. TRPV3/4 and Stroke TRPV4 is involved in the pathophysiological changes of both astrocytes and neurons after ischemia. In a global hypoxia/ischemia rat model, TRPV4 expression was increased gradually in astrocytes and decreased in neurons (Butenko et al., 2012), suggesting that TRPV4 Journal of Neuroscience Research

Brain TRP Channels and Stroke

may play a role in neuronal death during the acute phase of stroke and in astrogliosis during the chronic phase. In neurons, TRPV4 is activated by cell swelling, AA, or the epoxyeicosatrienoic acids (Plant and Strotmann, 2007), which are associated with cerebral ischemia. TRPV4 activation enhances Ca21 entry via NMDA receptors and requires the NR2B but not the NR2A subunit (Li et al., 2013). CaMKII but not protein kinase C or CKII is associated with TRPV4-mediated NR2B phosphorylation. Furthermore, activation of TRPV4 depolarizes the resting membrane potential (Shibasaki et al., 2007), which facilitates presynaptic glutamate release. Because Ca21 entry via NMDA receptors is the major pathway leading to neuronal death following stroke, TRPV4 activation worsens glutamate excitotoxicity. This is in contrast to the TRPC6 channel, which upon activation ameliorates NMDA-mediated excitotoxicity, even though both TRPV4 and TRPC6 are permeable to Ca21 ions. In addition to affecting NMDA receptors, Ca21 entry via TRPV4 also stimulates the production of ROS and nitric oxide (NO; Donko et al., 2010; Li et al., 2011; Bubolz et al., 2012), exacerbating neuronal injury following stroke. Therefore, blocking TRPV4 is likely to be neuroprotective after stroke, with a possible prominent effect in the acute stage. In astrocytes, both the expression and the activity of TRPV4 are enhanced gradually after stroke (Butenko et al., 2012). TRPV4 upregulation was observed at 1 hr and at 7 days after ischemia. Thus, it is likely to be involved in the process of astrogliosis. In astrocytes under hypoxic conditions, spontaneous [Ca21]i oscillations were found to increase, correlating with Ca21 entry via TRPV4 channels. Because Ca21 levels are crucial for a number of cellular functions, activation of TRPV4 is likely to affect the Ca21-dependent release of neurotransmitters, cytokines, and growth factors from reactive astrocytes following stroke. The role of TRPV3 in ischemic stroke was investigated by using a TRPV3 agonist, incensole acetate (IA; Moussaieff et al., 2012). IA is a Boswellia resin component that has been used for various medical purposes and exported as incense since ancient times. IA was discovered to be a selective activator of TRPV3, with no effect on other TRPV channels (Moussaieff et al., 2008). In a mouse tMCAO model (Moussaieff et al., 2012), IA treatment attenuated neurological deficits and produced a reduction in infarct volume. The neuroprotective effect was partially preserved in TRPV3 null mice, indicating that IA may exert its beneficial effects through pathways other than activating TRPV3. Further experiments are required to clarify the expression, activity, and functions of TRPV3 in stroke. TRP CHANNELS AND NEURONAL SURVIVAL AFTER STROKE After stroke, cytotoxicity of Ca21 overload is known to cause neuronal death. As discussed above, accumulating evidence has shown that TRP channels are vigorously Journal of Neuroscience Research

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Fig. 1. Interactions between various TRP channels and other Ca21 entry pathways in neurons after stroke and how these channels affect membrane potential, intracellular Ca21 and Na1 levels, and glutamate release. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

involved in this Ca21-induced neuronal death (Fig. 1). Among the neuronal TRP channels involved in stroke, TRPC4, TRPC6, and TRPV4 have a higher Ca21 selectivity over Na1, with the ratio of PCa/PNa > 5 (Cavalie, 2007; Dietrich and Gudermann, 2007; Plant and Strotmann, 2007), whereas TRPM2 and TRPC3 have a similar permeability for Ca21 and Na1, with the ratio of PCa/ PNa varying between 0.6 and 1.6 (Eder et al., 2007; Eisfeld and Luckhoff, 2007). TRPM7 is a unique divalent cation-selective channel with a high permeability for Mg21 and Ca21 (Penner and Fleig, 2007). After ischemia, malicious Ca21 entry via NMDA and other glutamate receptors elicits excitotoxicity. Ca21 influx via TRP channels will further increase [Ca21]i, leading to a number of consequences. First, higher [Ca21]i enhances the production of ROS, RNS, ADPR, H2O2, and AA, which further activates TRPM2 and M7 channels, serving as a positive feedback mechanism. Mg21 influx via TRPM7 by itself is toxic to cells. Second, with enhanced Na1 entry via TRPM2 and TRPC3 channels, higher [Ca21]i and [Na1]i levels depolarize membrane potential and activate voltage-gated calcium channels (VGCCs). Opening of VGCCs again increases [Ca21]i levels and promotes presynaptic neurotransmitter glutamate release. Higher glutamate secretion will improve NMDAR activities, worsening malicious Ca21 influx via NMDARs. In addition, higher [Na1]i levels could lead to cell swelling, further activate TRPV4 channels, and promote Ca21 entry (Plant and Strotmann, 2007). Third, Ca21 influx via NMDAR activates calpain, a cysteine protease, which degrades the TRPC6 channel. On the contrary, Ca21 entry via TRPC3 and TRPC6 may play a beneficial role. Proper functions of TRPC3 and TRPC6 channels after stroke can improve stroke outcome by increasing CREB phosphorylation

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Fig. 2. Routes of Ca21 entry into astrocytes following ischemic injury. Several routes have been identified, including ionotropic receptors such as NMDAR, 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propionate receptors, and P2X purinoceptors; reverse mode of Na1–Ca21 exchanger (NCX); and store-operated Ca21 entry possibly involving TRPC1, TRPC4, or TRPC5; and TRP channels. Although voltage-gated Ca21 channels VGCCs have been found in astrocytes, their significance in Ca21 entry has yet to be verified. In addition to Ca21 influx from extracellular space, Ca21 release from internal stores endoplasmic reticulum (ER) and mitochondria also contributes to the increase of [Ca21]i. The inositol 1,4,5-trisphosphate receptors are the major route for Ca21 release from ER, whereas NCX and the mitochondrial permeability transition pore are responsible for Ca21 efflux from mitochondria. The increase of [Ca21]i not only alters membrane potential but also affects a number of cellular functions, including the release of glutamate, ATP, and many other neurotrophic factors and cytokines. Furthermore, [Ca21]i also regulates astrocyte acid–base homeostasis by converting glycogen to glucose for anaerobic respiration under hypoxic conditions. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

and the production of BDNF and Bcl-2, which can inhibit NMDAR activities and attenuate apoptosis (Fig. 1; Jia et al., 2007; Kitagawa, 2007). Therefore, selectively inhibiting or enhancing certain TRP channels following stroke will increase the chance of neuronal survival. It is noteworthy that the neurons in the core of infarct die within minutes when blood supply is ceased completely. The neurons within the penumbra region undergo mild hypoxia and struggle to survive and are thereby the targets for neuroprotective treatments. The TRP channels in these neurons are ideal targets for developing novel treatments to improve cell survival. TRP CHANNELS AND ASTROCYTE SURVIVAL AFTER STROKE Unlike the case for neurons, only TRPC3 and TRPV4 have been investigated in astrocytes following stroke. Both channels exhibit enhanced activities and regulate

gliosis. For TRPV4, protein expression was observed immediately after stroke and was maintained through day 7 (Butenko et al., 2012), whereas, for TRPC3, thrombin leaked from vasculature upregulates TRPC3 expression (Shirakawa et al., 2010). Because they are permeable to Ca21 ions, TRPC3 and TRPV4 contribute to the increase of [Ca21]i in astrocytes following stroke (Fig. 2). Major sources for the increase of [Ca21]i in astrocytes include internal stores such as ER and mitochondria, ionotropic receptors such as NMDA and AMPA receptors and P2X purinoceptors, reversal of Na1–Ca21 exchanger, and SOCE (Verkhratsky et al., 2012). TRPC1 is likely the channel that mediates SOCE in astrocytes, but its functions in stroke have not been investigated. Although astrocyte functions are clearly necessary for neuronal health in normal physiology, certain functions have negative consequence on neuronal survival after stroke. A detailed discussion can be found in previous reviews (Vangeison and Rempe, 2009; Zhao and Rempe, 2010). After stroke, the increase of [Ca21]i plays a critical role in regulating various astrocyte functions, which includes the release of neurotransmitter glutamate, ATP, neurotrophic factors, MMPs, NO, and cytokines (Fig. 2). Intracellular Ca21 overload also regulates acid–base homeostasis by increasing the conversion of glycogen to glucose. As a result of a lack of oxygen after stroke, anaerobic respiration generates ATP and lactate, worsening acid–base imbalance. On the contrary, astrocytes uptake glutamate even in the early stage of stroke, yielding a neuroprotective effect. Therefore, temporal and subtle regulation of astrocyte functions after stroke will undoubtedly help in neuronal survival, particularly in the penumbra region. Identification of TRP channels in astrocytes will provide novel ways of regulating astrocyte functions by fine-tuning the intracellular Ca21 levels. CONCLUSIONS AND PERSPECTIVES With the increased understanding of the pathophysiology of stroke, there has been steady progress over the past 10 years in acute, preventive, and rehabilitative stroke treatments. Additionally, the involvement of TRP channels in stroke pathophysiology has been increasingly documented. TRPC3/4/6, TRPM2/4/7, and TRPV1/3/4 channels have been extensively investigated with a focus on their effects on neurons and the vascular endothelium following stroke. There have been few studies of TRP channels in other cell types. For example, immune cells, such as microglia, play an important role in stroke development (Chamorro et al., 2012; Sharma and Ping, 2014) and have attracted attention as possible targets for therapy. However, only TRPM2 has been studied in microglia. Even in neurons, the pathological roles of many TRP channels that are associated with numerous functions under physiological conditions remain unknown. An example is TRPC3, which is involved in many neuronal functions. However, studies of its role in neuronal death and regeneration after stroke are completely lacking. Journal of Neuroscience Research

Brain TRP Channels and Stroke

Therefore, understanding these channels in stroke not only will enrich our knowledge of stroke pathophysiology but also may provide novel therapeutic targets. Given that most TRP channels are Ca21 permeable or are regulated by [Ca21]i, these channels participate in the regulation of Ca21 homeostasis poststroke. However, the outcome of Ca21 influx via different TRP channels is variable. An example is the opposite effects on neuronal NMDA receptors that result from the opening of TRPC6 and TRPV4 during ischemia. Although differences in the activation mechanisms, channel electrophysiological properties, and downstream signaling pathways are proposed to contribute to opposite outcomes, critical questions, such as what level of [Ca21]i is beneficial for neuroprotection, must be addressed. By blocking or enhancing particular TRP channels, the fine tuning of Ca21 homeostasis can be pivotal for therapeutic outcomes. It is noteworthy that many TRP channels are ubiquitously expressed. Therefore, the potential side effects of targeting TRP channels for stroke therapy should be carefully examined. Future studies attempting to unify expression, function, regulation, and adverse effects will allow a more comprehensive understanding of the roles of TRP channels in stroke, which will ultimately lead to the development of new therapeutic strategies. ACKNOWLEDGMENTS The authors have no conflicts of interest. REFERENCES Aarts M, Iihara K, Wei WL, Xiong ZG, Arundine M, Cerwinski W, MacDonald JF, Tymianski M. 2003. A key role for TRPM7 channels in anoxic neuronal death. Cell 115:863–877. Akabori H, Yamamoto H, Tsuchihashi H, Mori T, Fujino K, Shimizu T, Endo Y, Tani T. 2007. Transient receptor potential vanilloid 1 antagonist, capsazepine, improves survival in a rat hemorrhagic shock model. Ann Surg 245:964–970. Akita T, Okada Y. 2011. Regulation of bradykinin-induced activation of volume-sensitive outwardly rectifying anion channels by Ca21 nanodomains in mouse astrocytes. J Physiol 589:3909–3927. Alessandri-Haber N, Yeh JJ, Boyd AE, Parada CA, Chen X, Reichling DB, Levine JD. 2003. Hypotonicity induces TRPV4-mediated nociception in rat. Neuron 39:497–511. Alessandri-Haber N, Dina OA, Yeh JJ, Parada CA, Reichling DB, Levine JD. 2004. Transient receptor potential vanilloid 4 is essential in chemotherapy-induced neuropathic pain in the rat. J Neurosci 24: 4444–4452. Alessandri-Haber N, Dina OA, Chen X, Levine JD. 2009. TRPC1 and TRPC6 channels cooperate with TRPV4 to mediate mechanical hyperalgesia and nociceptor sensitization. J Neurosci 29:6217–6228. Atiba-Davies M, Noben-Trauth K. 2007. TRPML3 and hearing loss in the varitint-waddler mouse. Biochim Biophys Acta 1772:1028–1031. Bai JZ, Lipski J. 2010. Differential expression of TRPM2 and TRPV4 channels and their potential role in oxidative stress-induced cell death in organotypic hippocampal culture. Neurotoxicology 31:204–214. Barbet G, Demion M, Moura IC, Serafini N, Leger T, Vrtovsnik F, Monteiro RC, Guinamard R, Kinet JP, Launay P. 2008. The calciumactivated nonselective cation channel TRPM4 is essential for the migration but not the maturation of dendritic cells. Nat Immunol 9:1148– 1156. Journal of Neuroscience Research

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