Channels
ISSN: 1933-6950 (Print) 1933-6969 (Online) Journal homepage: http://www.tandfonline.com/loi/kchl20
ATP-sensitive potassium channels and vascular function Qadeer Aziz, Yiwen Li & Andrew Tinker To cite this article: Qadeer Aziz, Yiwen Li & Andrew Tinker (2015) ATP-sensitive potassium channels and vascular function, Channels, 9:1, 3-4, DOI: 10.1080/19336950.2015.1004289 To link to this article: http://dx.doi.org/10.1080/19336950.2015.1004289
Accepted author version posted online: 09 Feb 2015.
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Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=kchl20 Download by: [Nanyang Technological University]
Date: 09 November 2015, At: 21:01
AUTOCOMMENTARY Channels 9:1, 3--4; January/February 2015; © 2015 Taylor & Francis Group, LLC
ATP-sensitive potassium channels and vascular function Qadeer Aziz, Yiwen Li, and Andrew Tinker*
Downloaded by [Nanyang Technological University] at 21:01 09 November 2015
The Heart Center; William Harvey Research Institute; Barts & The London School of Medicine & Dentistry; London, UK
Keywords: ATP-sensitive potassium channel; hypertension; inward rectifier; sudden cardiac death vascular smooth muscle. *Correspondence to: [email protected]
Andrew
Tinker;
E-mail:
Submitted: 09/26/2014 Accepted: 09/28/2014 http://dx.doi.org/10.1080/19336950.2015.1004289 Autocommentary to: Aziz Q, et al. The ATP-Sensitive Potassium Channel Subunit, Kir6.1, in Vascular Smooth Muscle Plays a Major Role in Blood Pressure Control. Hypertension. 2014; 64(3):523–9. http://dx. doi/10.1161/HYPERTENSIONAHA.114.03116
www.landesbioscience.com
ATP-sensitive potassium channels (KATP) are widely distributed in different organs of the body. They are best described in pancreatic b cells and cardiac myocytes but are also present in the peripheral and central nervous system and in vascular and non-vascular smooth muscle. As implied by the name they are sensitive to cellular metabolism and open in response to falling ATP:ADP ratio.1 The channels are a complex of 4 sulphonylurea receptors (SUR) and 4 inward rectifier Kir6x subunits. Cloning of the relevant subunits has allowed modern murine genetic targeting strategies to be used to understand the physiological and pathophysiological function of these channels.1 The tone of vascular smooth muscle (VSM) cells is important in determining blood pressure and in matching blood flow in an individual vascular bed to metabolic demand. There is a substantial literature showing the involvement of KATP channels in these processes.1 Direct activation of these channels during tissue ischemia leads to hyperpolarisation, decreased calcium entry via L-type calcium channels and vasorelaxation, hence increasing tissue perfusion. However, these channels are also subject to prominent hormonal regulation. Vasodilators, such as adenosine and calcitonin gene related peptide, activate their cognate G-protein coupled receptors to activate stimulatory G-proteins, increase cellular levels of cAMP and activate protein kinase A, which directly phosphorylates the channel leading to increased channel activity.1,2 Vasoconstrictors such as angiotensin II inhibit channel activity via protein kinase C2. Studies on the metabolic sensitivity and single-channel properties of these channels revealed differences from those present in for example ventricular cardiac myocytes. Channels
The single-channel conductance was lower at »35 pS compared to »70 pS and the channels showed an absolute dependency on the availability of nucleotide diphosphates and a lower affinity to ATP inhibition. This suggested a unique molecular composition and was supported by subsequent studies showing that in heterologous expression systems SUR2B\Kir6.1 recapitulated the native current in VSM cells.3 A number of groups generated mice with gobal genetic deletion of Kir6.1 (kcnj8) and SUR2 (abcc9) and they revealed an intriguing phenotype.4,5 Both strains of mice died suddenly from what appeared to be coronary artery spasm replicating severe versions of human Prinzmetal angina. Furthermore, SUR2 knockout mice were hypertensive. It was initially assumed that this arose from the critical role of KATP channels in VSM cell function. However, selective transgenic expression of SUR2B in VSM in SUR2 knockout mice led to reconstitution of the KATP current but no change in the sudden death phenotype suggesting profound VSM extrinsic influences in determining this aspect of the phenotype.6 In order to clarify the role of VSM KATP channels and that of the Kir6.1 subunit specifically, we recently developed a murine model in which it was possible to conditionally delete Kir6.1 in smooth muscle. We engineered loxP sites around exon 2 of the kncj8 gene and crossed this with a mouse expressing cre recombinase driven by the SM22 promoter which expresses selectively in muscle (and in our hands relatively selectively in smooth muscle with little evidence of cellular mosaicism).7 This enabled the generation of mice with conditional deletion of kcnj8 in smooth muscle. This corresponded with 3
Downloaded by [Nanyang Technological University] at 21:01 09 November 2015
an absence of KATP currents in a number of vascular beds. We compared the integrated cardiovascular phenotype of these mice with those having global genetic deletion of kcnj8. Using in-vivo telemetric recordings we demonstrated both lines of mice were spontaneously hypertensive though interestingly, global knockout mice had a larger increase in blood pressure. However, the mice with conditional smooth muscle deletion were not predisposed to sudden death and this could not be provoked even after the administration of ergonovine, a potent constrictor of smooth muscle.7 What are the implications of these results? They suggest that Kir6.1 in VSM cells does indeed have an important role in determining resting blood pressure and tone particularly in resistance vessels. However, Kir6.1 must also have a role in other tissues. There are data suggesting that KATP channels are present in endothelial cells and are formed of a heteromultimer of Kir6.1 and Kir6.2 and may modulate vascular tone via endothelin-1
4
release.8 We are actively pursuing these possibilities using similar conditional deletion strategies. It is generally assumed that Kir6.2 with SUR2A is the major isoform underlying KATP currents in cardiac myocytes. However, the focus has been very much on ventricular cells and recent studies have indicated much more potential heterogeneity in subunit composition in the atria and specialized conducting tissues. The mice with global genetic deletion of kcnj8 die from heart block and sinoatrial nodal failure. Thus, it is possible Kir6.1-containing KATP channels may be playing a role in cellular protection in sinoatrial and atrioventricular nodes. Finally, integrated cardiovascular function is also determined by a number of reflex arcs mediated through control regions in the brainstem, peripheral nerves and ganglia. KATP channels are present in many neuronal populations and these need to be excluded as playing a role. Our own feeling is that to fully recapitulate the phenotype of the global knockout mouse, deletion in a number of tissues might be
Channels
necessary, reflecting additive contributions to the physiology of the Kir6.1 subunit in each. Disclosure of Potential Conflicts of Interest No potential conflicts of interest were disclosed. References 1. Tinker A. et al. Br J Pharmacol 2014; 171:12-23; PMID:24102106; http://dx.doi.org/10.1111/bph.12407 2. Rodrigo GC. et al. Curr Pharm Des 2005; 11:1915-40; http://dx.doi.org/10.2174/1381612054021015 3. Yamada M. et al. J Physiol Lond 1997 499:715-20; PMID:9130167; http://dx.doi.org/10.1113/jphysiol.1997. sp021963 4. Miki T. et al. Nat Med 2002 8:466-72; PMID:11984590; http://dx.doi.org/10.1038/nm0502-466 5. Chutkow WA. et al. J Clin Invest 2002 110:203-8; PMID:12122112; http://dx.doi.org/10.1172/JCI0215672 6. Kakkar R. et al. Circ Res 2006 98:682-9; PMID:16456098; http://dx.doi.org/10.1161/01.RES.0000207498.40005.e7 7. Aziz Q. et al. Hypertension 2014 64:523-9; PMID:24914196; http://dx.doi.org/10.1161/HYPERTENSIONAHA.114. 03116 8. Malester B. et al. FASEB J 2007 21:2162-72; PMID:17341678; http://dx.doi.org/10.1096/fj.06-7821com
Volume 9 Issue 1
ISSN: 1933-6950 (Print) 1933-6969 (Online) Journal homepage: http://www.tandfonline.com/loi/kchl20
ATP-sensitive potassium channels and vascular function Qadeer Aziz, Yiwen Li & Andrew Tinker To cite this article: Qadeer Aziz, Yiwen Li & Andrew Tinker (2015) ATP-sensitive potassium channels and vascular function, Channels, 9:1, 3-4, DOI: 10.1080/19336950.2015.1004289 To link to this article: http://dx.doi.org/10.1080/19336950.2015.1004289
Accepted author version posted online: 09 Feb 2015.
Submit your article to this journal
Article views: 218
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=kchl20 Download by: [Nanyang Technological University]
Date: 09 November 2015, At: 21:01
AUTOCOMMENTARY Channels 9:1, 3--4; January/February 2015; © 2015 Taylor & Francis Group, LLC
ATP-sensitive potassium channels and vascular function Qadeer Aziz, Yiwen Li, and Andrew Tinker*
Downloaded by [Nanyang Technological University] at 21:01 09 November 2015
The Heart Center; William Harvey Research Institute; Barts & The London School of Medicine & Dentistry; London, UK
Keywords: ATP-sensitive potassium channel; hypertension; inward rectifier; sudden cardiac death vascular smooth muscle. *Correspondence to: [email protected]
Andrew
Tinker;
E-mail:
Submitted: 09/26/2014 Accepted: 09/28/2014 http://dx.doi.org/10.1080/19336950.2015.1004289 Autocommentary to: Aziz Q, et al. The ATP-Sensitive Potassium Channel Subunit, Kir6.1, in Vascular Smooth Muscle Plays a Major Role in Blood Pressure Control. Hypertension. 2014; 64(3):523–9. http://dx. doi/10.1161/HYPERTENSIONAHA.114.03116
www.landesbioscience.com
ATP-sensitive potassium channels (KATP) are widely distributed in different organs of the body. They are best described in pancreatic b cells and cardiac myocytes but are also present in the peripheral and central nervous system and in vascular and non-vascular smooth muscle. As implied by the name they are sensitive to cellular metabolism and open in response to falling ATP:ADP ratio.1 The channels are a complex of 4 sulphonylurea receptors (SUR) and 4 inward rectifier Kir6x subunits. Cloning of the relevant subunits has allowed modern murine genetic targeting strategies to be used to understand the physiological and pathophysiological function of these channels.1 The tone of vascular smooth muscle (VSM) cells is important in determining blood pressure and in matching blood flow in an individual vascular bed to metabolic demand. There is a substantial literature showing the involvement of KATP channels in these processes.1 Direct activation of these channels during tissue ischemia leads to hyperpolarisation, decreased calcium entry via L-type calcium channels and vasorelaxation, hence increasing tissue perfusion. However, these channels are also subject to prominent hormonal regulation. Vasodilators, such as adenosine and calcitonin gene related peptide, activate their cognate G-protein coupled receptors to activate stimulatory G-proteins, increase cellular levels of cAMP and activate protein kinase A, which directly phosphorylates the channel leading to increased channel activity.1,2 Vasoconstrictors such as angiotensin II inhibit channel activity via protein kinase C2. Studies on the metabolic sensitivity and single-channel properties of these channels revealed differences from those present in for example ventricular cardiac myocytes. Channels
The single-channel conductance was lower at »35 pS compared to »70 pS and the channels showed an absolute dependency on the availability of nucleotide diphosphates and a lower affinity to ATP inhibition. This suggested a unique molecular composition and was supported by subsequent studies showing that in heterologous expression systems SUR2B\Kir6.1 recapitulated the native current in VSM cells.3 A number of groups generated mice with gobal genetic deletion of Kir6.1 (kcnj8) and SUR2 (abcc9) and they revealed an intriguing phenotype.4,5 Both strains of mice died suddenly from what appeared to be coronary artery spasm replicating severe versions of human Prinzmetal angina. Furthermore, SUR2 knockout mice were hypertensive. It was initially assumed that this arose from the critical role of KATP channels in VSM cell function. However, selective transgenic expression of SUR2B in VSM in SUR2 knockout mice led to reconstitution of the KATP current but no change in the sudden death phenotype suggesting profound VSM extrinsic influences in determining this aspect of the phenotype.6 In order to clarify the role of VSM KATP channels and that of the Kir6.1 subunit specifically, we recently developed a murine model in which it was possible to conditionally delete Kir6.1 in smooth muscle. We engineered loxP sites around exon 2 of the kncj8 gene and crossed this with a mouse expressing cre recombinase driven by the SM22 promoter which expresses selectively in muscle (and in our hands relatively selectively in smooth muscle with little evidence of cellular mosaicism).7 This enabled the generation of mice with conditional deletion of kcnj8 in smooth muscle. This corresponded with 3
Downloaded by [Nanyang Technological University] at 21:01 09 November 2015
an absence of KATP currents in a number of vascular beds. We compared the integrated cardiovascular phenotype of these mice with those having global genetic deletion of kcnj8. Using in-vivo telemetric recordings we demonstrated both lines of mice were spontaneously hypertensive though interestingly, global knockout mice had a larger increase in blood pressure. However, the mice with conditional smooth muscle deletion were not predisposed to sudden death and this could not be provoked even after the administration of ergonovine, a potent constrictor of smooth muscle.7 What are the implications of these results? They suggest that Kir6.1 in VSM cells does indeed have an important role in determining resting blood pressure and tone particularly in resistance vessels. However, Kir6.1 must also have a role in other tissues. There are data suggesting that KATP channels are present in endothelial cells and are formed of a heteromultimer of Kir6.1 and Kir6.2 and may modulate vascular tone via endothelin-1
4
release.8 We are actively pursuing these possibilities using similar conditional deletion strategies. It is generally assumed that Kir6.2 with SUR2A is the major isoform underlying KATP currents in cardiac myocytes. However, the focus has been very much on ventricular cells and recent studies have indicated much more potential heterogeneity in subunit composition in the atria and specialized conducting tissues. The mice with global genetic deletion of kcnj8 die from heart block and sinoatrial nodal failure. Thus, it is possible Kir6.1-containing KATP channels may be playing a role in cellular protection in sinoatrial and atrioventricular nodes. Finally, integrated cardiovascular function is also determined by a number of reflex arcs mediated through control regions in the brainstem, peripheral nerves and ganglia. KATP channels are present in many neuronal populations and these need to be excluded as playing a role. Our own feeling is that to fully recapitulate the phenotype of the global knockout mouse, deletion in a number of tissues might be
Channels
necessary, reflecting additive contributions to the physiology of the Kir6.1 subunit in each. Disclosure of Potential Conflicts of Interest No potential conflicts of interest were disclosed. References 1. Tinker A. et al. Br J Pharmacol 2014; 171:12-23; PMID:24102106; http://dx.doi.org/10.1111/bph.12407 2. Rodrigo GC. et al. Curr Pharm Des 2005; 11:1915-40; http://dx.doi.org/10.2174/1381612054021015 3. Yamada M. et al. J Physiol Lond 1997 499:715-20; PMID:9130167; http://dx.doi.org/10.1113/jphysiol.1997. sp021963 4. Miki T. et al. Nat Med 2002 8:466-72; PMID:11984590; http://dx.doi.org/10.1038/nm0502-466 5. Chutkow WA. et al. J Clin Invest 2002 110:203-8; PMID:12122112; http://dx.doi.org/10.1172/JCI0215672 6. Kakkar R. et al. Circ Res 2006 98:682-9; PMID:16456098; http://dx.doi.org/10.1161/01.RES.0000207498.40005.e7 7. Aziz Q. et al. Hypertension 2014 64:523-9; PMID:24914196; http://dx.doi.org/10.1161/HYPERTENSIONAHA.114. 03116 8. Malester B. et al. FASEB J 2007 21:2162-72; PMID:17341678; http://dx.doi.org/10.1096/fj.06-7821com
Volume 9 Issue 1
