Channels
ISSN: 1933-6950 (Print) 1933-6969 (Online) Journal homepage: http://www.tandfonline.com/loi/kchl20
Keeping the balance Susanne tom Dieck To cite this article: Susanne tom Dieck (2013) Keeping the balance, Channels, 7:6, 418-419, DOI: 10.4161/chan.26925 To link to this article: http://dx.doi.org/10.4161/chan.26925
Copyright © 2013 Landes Bioscience
Published online: 15 Nov 2013.
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Date: 12 September 2015, At: 16:58
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Channels 7:6, 418–419; November/December 2013; © 2013 Landes Bioscience
Channels News & Views Keeping the balance Comment on: Liu X, et al. Channels (Austin) 2013; 7; PMID:24064553; http://dx.doi.org/10.4161/chan.26376 Comment on: Knoflach D, et al. Channels (Austin) 2013; 7; PMID:24051672; http://dx.doi.org/10.4161/chan.26368
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Susanne tom Dieck Max-Planck-Institute for Brain Research; Synaptic Plasticity Department; Frankfurt, Germany Email: [email protected]; http://dx.doi.org/10.1614/chan.26925
How we see our environment is the result of a multi-level, parallel processing effort by the central nervous system. This computation is initiated within the retina at the very first synapse in the visual pathway— the photoreceptor ribbon synapse. Two recent studies shed light on the critical role of balanced calcium channel activity in maturation of this highly specialized synapse.1, 2 Photoreceptors face the challenge of reporting spatio-temporal changes of light stimuli in the context of background lighting that ranges over many orders of magnitude. Besides sharing the job between 2 classes of photoreceptors—the rod photoreceptors for low light conditions and cone photoreceptors for brighter conditions—they do so by
continuously transmitting a signal that is adjusted to light input. The capacity for this sustained transmission comes from an elaborate cytomatrix structure—the ribbon—that lines the active zone and tethers hundreds of synaptic vesicles. 3 Clearly, the relentless synaptic activity whereby changes in membrane potential are translated into corresponding changes of vesicle release also requires a calcium channel with special characteristics. Indeed the voltage-gated calcium channel at rod spherules and—although somewhat more debated - at cone pedicles1 is a specialized L-type channel with very slow Ca2+-mediated inactivation kinetics containing the pore-forming α subunit Cacna1f.4 As with other protein families
with specialized members at photoreceptor synapses, the expression pattern of Cacna1f is highly restricted and so far only shown convincingly in retina and the immune system. In human, a plethora of mutations have been detected in CACNA1F and most of them are associated with incomplete congenital stationary night blindness type 2 (CSNB2).4 The name incomplete CSNB2 reflects partial non-progressive impairment of vision under dim lighting conditions, but is inadequate in that vision in welllit environments is also affected. Hence night vision problems are not the major report of patients but rather decreased visual acuity, myopia and nystagmus. The non-progressive nature of CSNB is scientifically useful: in contrast to genetic
Figure 1. Ribbon synapse maturation defects in CSNB2 model mouse lines. In the presence of wild-type Cacna1f and the channel activating protein Cabp4, calcium channel activity spans the full dynamic range and leads to fully mature ribbon complexes which have a characteristic horseshoe shape. Various mouse lines with a Cacna1f loss—either expressing only truncated protein or very low levels—show a severe morphological alteration of the ribbon structure with an immature phenotype. Mostly immature ribbons are also found in the Cabp4 knock out where Cacna1f activity is reduced and in the I745T mutant line where excitability is increased. A slight progression in ribbon synapse maturity indicates that there are at least two calcium channel dependent maturation steps. 418
Channels
Volume 7 Issue 6
NEWS & VIEWS
Downloaded by [Florida State University] at 16:58 12 September 2015
Paper Type
disorders leading to rapid photoreceptor degeneration, the synaptopathies related to CSNB are not overwhelmed by more extensive retinal deterioration. Accordingly detailed investigations of the mechanisms underlying CSNB2 and mutations in presynaptic proteins that phenocopy CSNB2 have led to insights into synapse development, synaptic structure-function relationships and connectivity patterns in the retina. 5,6 Especially a tight connection between calcium channel localization, ribbon architecture, and synapse maturation became obvious. In 2005, severe visual problems in a New Zealand family turned out to be due to an I745T point mutation in CACNA1F.7 Strikingly some of the male family members presented in addition with intellectual disability and autism. The location of the CACNA1F gene on the X-chromosome provided a clue to the underlying molecular pathology. Whereas, in CSNB2, heterozygote females are clinically unaffected carriers, in the New Zealand family heterozygote females have significant visual difficulties. This dominant phenotype was consistent with the I745T mutation leading
to a gain-of-function. Indeed analysis in a heterologous expression system confirmed a gain-of-function in the form of much easier excitability of the channel8 and prompted the group to establish the mouse model now analyzed by Liu et al.,1 and Knoflach et al.2 The 2 studies show that several of the visual abnormalities found in the New Zealand family are reproduced in this mouse line including ERG b-wave reduction and difficulties in visual orientation. Furthermore they provide insights into the conundrum that loss- and gain-of-function mutations lead to similar visual difficulties and ERG aberrations; they suggest that ribbon synapse maturation proceeds at least in 2 steps and depends not only on the presence of the calcium channel protein but in a later step also on balanced activity. Both hypo- and hyperactivated channels accomplished respectively by deletion of the calcium channel regulator Cabp4 and the Cacna1f I745T mutation lead to an improper maturation of the synapse architecture (Fig. 1). Most likely in both situations the full dynamic range of photoreceptor glutamate release would not be achieved. Undoubtedly future use of
this Cacna1f mouse model will untangle the molecular events leading to the maturation defects. Likewise the potential mosaicism of channel activity in heterozygote female mice from Cacna1f mutant lines, as a consequence of X-chromosome inactivation, is a yet unexploited opportunity to understand synapse maturation, synaptic transmission and retinal wiring. References Liu X, et al. Channels (Austin) 2013; 7: (Forthcoming); PMID:24064553; http://dx.doi.org/10.4161/ chan.26376 2. Knoflach D, et al. Channels (Austin) 2013; 7: (Forthcoming); PMID:24051672; http://dx.doi. org/10.4161/chan.26368 3. Regus-Leidig H, et al. Acta Physiol (Oxf ) 2012; 204:479-86; PMID:21880116; http://dx.doi. org/10.1111/j.1748-1716.2011.02355.x 4. Doering CJ, et al. Channels (Austin) 2007; 1:310; PMID:19151588; http://dx.doi.org/10.4161/ chan.3938 5. Haeseleer F, et al. Nat Neurosci 2004; 7:1079-87; PMID:15452577; http://dx.doi.org/10.1038/nn1320 6. Specht D, et al. Invest Ophthalmol Vis Sci 2009; 50:505-15; PMID:18952919; http://dx.doi. org/10.1167/iovs.08-2758 7. Hope CI, et al. Clin Experiment Ophthalmol 2005; 33:129-36; PMID:15807819; http://dx.doi. org/10.1111/j.1442-9071.2005.00987.x 8. Hemara-Wahanui A, et al. Proc Natl Acad Sci U S A 2005; 102:7553-8; PMID:15897456; http://dx.doi. org/10.1073/pnas.0501907102 1.
www.landesbioscience.com Channels
419
ISSN: 1933-6950 (Print) 1933-6969 (Online) Journal homepage: http://www.tandfonline.com/loi/kchl20
Keeping the balance Susanne tom Dieck To cite this article: Susanne tom Dieck (2013) Keeping the balance, Channels, 7:6, 418-419, DOI: 10.4161/chan.26925 To link to this article: http://dx.doi.org/10.4161/chan.26925
Copyright © 2013 Landes Bioscience
Published online: 15 Nov 2013.
Submit your article to this journal
Article views: 98
View related articles
Citing articles: 1 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=kchl20 Download by: [Florida State University]
Date: 12 September 2015, At: 16:58
Paper Type
Channels 7:6, 418–419; November/December 2013; © 2013 Landes Bioscience
Channels News & Views Keeping the balance Comment on: Liu X, et al. Channels (Austin) 2013; 7; PMID:24064553; http://dx.doi.org/10.4161/chan.26376 Comment on: Knoflach D, et al. Channels (Austin) 2013; 7; PMID:24051672; http://dx.doi.org/10.4161/chan.26368
Downloaded by [Florida State University] at 16:58 12 September 2015
Susanne tom Dieck Max-Planck-Institute for Brain Research; Synaptic Plasticity Department; Frankfurt, Germany Email: [email protected]; http://dx.doi.org/10.1614/chan.26925
How we see our environment is the result of a multi-level, parallel processing effort by the central nervous system. This computation is initiated within the retina at the very first synapse in the visual pathway— the photoreceptor ribbon synapse. Two recent studies shed light on the critical role of balanced calcium channel activity in maturation of this highly specialized synapse.1, 2 Photoreceptors face the challenge of reporting spatio-temporal changes of light stimuli in the context of background lighting that ranges over many orders of magnitude. Besides sharing the job between 2 classes of photoreceptors—the rod photoreceptors for low light conditions and cone photoreceptors for brighter conditions—they do so by
continuously transmitting a signal that is adjusted to light input. The capacity for this sustained transmission comes from an elaborate cytomatrix structure—the ribbon—that lines the active zone and tethers hundreds of synaptic vesicles. 3 Clearly, the relentless synaptic activity whereby changes in membrane potential are translated into corresponding changes of vesicle release also requires a calcium channel with special characteristics. Indeed the voltage-gated calcium channel at rod spherules and—although somewhat more debated - at cone pedicles1 is a specialized L-type channel with very slow Ca2+-mediated inactivation kinetics containing the pore-forming α subunit Cacna1f.4 As with other protein families
with specialized members at photoreceptor synapses, the expression pattern of Cacna1f is highly restricted and so far only shown convincingly in retina and the immune system. In human, a plethora of mutations have been detected in CACNA1F and most of them are associated with incomplete congenital stationary night blindness type 2 (CSNB2).4 The name incomplete CSNB2 reflects partial non-progressive impairment of vision under dim lighting conditions, but is inadequate in that vision in welllit environments is also affected. Hence night vision problems are not the major report of patients but rather decreased visual acuity, myopia and nystagmus. The non-progressive nature of CSNB is scientifically useful: in contrast to genetic
Figure 1. Ribbon synapse maturation defects in CSNB2 model mouse lines. In the presence of wild-type Cacna1f and the channel activating protein Cabp4, calcium channel activity spans the full dynamic range and leads to fully mature ribbon complexes which have a characteristic horseshoe shape. Various mouse lines with a Cacna1f loss—either expressing only truncated protein or very low levels—show a severe morphological alteration of the ribbon structure with an immature phenotype. Mostly immature ribbons are also found in the Cabp4 knock out where Cacna1f activity is reduced and in the I745T mutant line where excitability is increased. A slight progression in ribbon synapse maturity indicates that there are at least two calcium channel dependent maturation steps. 418
Channels
Volume 7 Issue 6
NEWS & VIEWS
Downloaded by [Florida State University] at 16:58 12 September 2015
Paper Type
disorders leading to rapid photoreceptor degeneration, the synaptopathies related to CSNB are not overwhelmed by more extensive retinal deterioration. Accordingly detailed investigations of the mechanisms underlying CSNB2 and mutations in presynaptic proteins that phenocopy CSNB2 have led to insights into synapse development, synaptic structure-function relationships and connectivity patterns in the retina. 5,6 Especially a tight connection between calcium channel localization, ribbon architecture, and synapse maturation became obvious. In 2005, severe visual problems in a New Zealand family turned out to be due to an I745T point mutation in CACNA1F.7 Strikingly some of the male family members presented in addition with intellectual disability and autism. The location of the CACNA1F gene on the X-chromosome provided a clue to the underlying molecular pathology. Whereas, in CSNB2, heterozygote females are clinically unaffected carriers, in the New Zealand family heterozygote females have significant visual difficulties. This dominant phenotype was consistent with the I745T mutation leading
to a gain-of-function. Indeed analysis in a heterologous expression system confirmed a gain-of-function in the form of much easier excitability of the channel8 and prompted the group to establish the mouse model now analyzed by Liu et al.,1 and Knoflach et al.2 The 2 studies show that several of the visual abnormalities found in the New Zealand family are reproduced in this mouse line including ERG b-wave reduction and difficulties in visual orientation. Furthermore they provide insights into the conundrum that loss- and gain-of-function mutations lead to similar visual difficulties and ERG aberrations; they suggest that ribbon synapse maturation proceeds at least in 2 steps and depends not only on the presence of the calcium channel protein but in a later step also on balanced activity. Both hypo- and hyperactivated channels accomplished respectively by deletion of the calcium channel regulator Cabp4 and the Cacna1f I745T mutation lead to an improper maturation of the synapse architecture (Fig. 1). Most likely in both situations the full dynamic range of photoreceptor glutamate release would not be achieved. Undoubtedly future use of
this Cacna1f mouse model will untangle the molecular events leading to the maturation defects. Likewise the potential mosaicism of channel activity in heterozygote female mice from Cacna1f mutant lines, as a consequence of X-chromosome inactivation, is a yet unexploited opportunity to understand synapse maturation, synaptic transmission and retinal wiring. References Liu X, et al. Channels (Austin) 2013; 7: (Forthcoming); PMID:24064553; http://dx.doi.org/10.4161/ chan.26376 2. Knoflach D, et al. Channels (Austin) 2013; 7: (Forthcoming); PMID:24051672; http://dx.doi. org/10.4161/chan.26368 3. Regus-Leidig H, et al. Acta Physiol (Oxf ) 2012; 204:479-86; PMID:21880116; http://dx.doi. org/10.1111/j.1748-1716.2011.02355.x 4. Doering CJ, et al. Channels (Austin) 2007; 1:310; PMID:19151588; http://dx.doi.org/10.4161/ chan.3938 5. Haeseleer F, et al. Nat Neurosci 2004; 7:1079-87; PMID:15452577; http://dx.doi.org/10.1038/nn1320 6. Specht D, et al. Invest Ophthalmol Vis Sci 2009; 50:505-15; PMID:18952919; http://dx.doi. org/10.1167/iovs.08-2758 7. Hope CI, et al. Clin Experiment Ophthalmol 2005; 33:129-36; PMID:15807819; http://dx.doi. org/10.1111/j.1442-9071.2005.00987.x 8. Hemara-Wahanui A, et al. Proc Natl Acad Sci U S A 2005; 102:7553-8; PMID:15897456; http://dx.doi. org/10.1073/pnas.0501907102 1.
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419
