The Ca<sub>V</sub>1.4 Calcium Channel: More Than Meets the Eye

Doering, Clinton J.; Peloquin, Jean B.; McRory, John E.

doi:10.4161/chan.3938

Cited by 26 publications

(22 citation statements)

References 77 publications

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“…Considering that a number of CSNB2 mutations in CACNA1F are predicted to yield dysfunctional channels rather than cause the complete absence of channel expression, 43 , 44 our findings reveal that alterations in PR synapse development may be a common feature of CSNB2, and that therapeutic interventions for offsetting visual impairment may require early targeting of the synaptopathic consequences of the mutations.…”

Section: Discussionmentioning

confidence: 80%

Dysregulation of Ca_v1.4 channels disrupts the maturation of photoreceptor synaptic ribbons in congenital stationary night blindness type 2

et al. 2013

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Mutations in the gene encoding Cav1.4, CACNA1F, are associated with visual disorders including X-linked incomplete congenital stationary night blindness type 2 (CSNB2). In mice lacking Cav1.4 channels, there are defects in the development of “ribbon” synapses formed between photoreceptors (PRs) and second-order neurons. However, many CSNB2 mutations disrupt the function rather than expression of Cav1.4 channels. Whether defects in PR synapse development due to altered Cav1.4 function are common features contributing to the pathogenesis of CSNB2 is unknown. To resolve this issue, we profiled changes in the subcellular distribution of Cav1.4 channels and synapse morphology during development in wild-type (WT) mice and mouse models of CSNB2. Using Cav1.4-selective antibodies, we found that Cav1.4 channels associate with ribbon precursors early in development and are concentrated at both rod and cone PR synapses in the mature retina. In mouse models of CSNB2 in which the voltage-dependence of Cav1.4 activation is either enhanced (Cav1.4I756T) or inhibited (CaBP4 KO), the initial stages of PR synaptic ribbon formation are largely unaffected. However, after postnatal day 13, many PR ribbons retain the immature morphology. This synaptic abnormality corresponds in severity to the defect in synaptic transmission in the adult mutant mice, suggesting that lack of sufficient mature synapses contributes to vision impairment in Cav1.4I756T and CaBP4 KO mice. Our results demonstrate the importance of proper Cav1.4 function for efficient PR synapse maturation, and that dysregulation of Cav1.4 channels in CSNB2 may have synaptopathic consequences.

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Section: Discussionmentioning

confidence: 80%

Dysregulation of Ca_v1.4 channels disrupts the maturation of photoreceptor synaptic ribbons in congenital stationary night blindness type 2

et al. 2013

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“…13,20,[52][53][54] Ca V 1.4 is largely restricted to the retina. 13,20,55,56 Ca V 2.1, Ca V 2.2, and Ca V 2.3 are found throughout the central and peripheral nervous systems. 13,21,22,57 In particular, Ca V 2.1 and Ca V 2.2 play key roles in the modulation of neurotransmitter release.…”

Section: O C C U R R E N C Ementioning

confidence: 99%

“…Consequently, they have prominent roles in the function of nerve and muscle 11,13,21,57 and also play important roles in hormone secretion from adrenal 52 and pancreatic cells. 53 Mutations in Ca V s are linked to a wide range of human diseases and syndromes that include hypokalemic periodic paralysis (Ca V 1.1) 55 ; cardiac arrhythmias and autism (Ca V 1.2) 60 ; stationary night blindness (Ca V 1.4) 55,56 ; and migraine (Ca V 2.1).…”

Section: B I O L O G I C a L F U N C T I O Nmentioning

confidence: 99%

Calmodulin Interactions withCa_v1 andCa_v2 Voltage‐Gated Calcium ChannelIQDomains

Kim

Findeisen

Minor

2011

Encyclopedia of Inorganic and Bioinorganic Chemistry

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High‐voltage‐activated calcium channels (Ca V 1s and Ca V 2s) are transmembrane protein complexes that couple membrane depolarization to cellular calcium entry. Because calcium is an intracellular messenger and Ca V s are important calcium sources, Ca V s have a key role in the conversion of electrical signals into the chemical signaling cascades that drive a variety of vital physiological processes in nerve and muscle. These include excitation‐contraction coupling, hormone release, gene regulation, and synaptic transmission. Ca V s are regulated by a diverse set of feedback mechanisms. Two important forms of activity‐dependent feedback modulation involve interactions between calcium‐calmodulin (Ca 2+ /CaM) and the Ca V α 1 pore‐forming subunit of Ca V 1s and Ca V 2s: calcium‐dependent inactivation (CDI) in which calcium influx promotes channel closing following activation, and calcium‐dependent facilitation (CDF), a process that enhances channel opening in response to elevated cytoplasmic calcium. The main site of action for Ca 2+ /CaM is a motif, known as an IQ domain , located on the C‐terminal cytoplasmic tail of the Ca V α 1 pore‐forming subunit. Strikingly, different Ca 2+ /CaM lobes are responsible for CDI and CDF in Ca V 1 and Ca V 2 channels. Crystallographic studies have indicated a structural basis for the apparent inversion of lobe‐specific roles in CDI and CDF in which Ca 2+ /CaM binds Ca V 1 and Ca V 2 IQ domains in opposite orientations.

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“…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).…”

Section: Keeping the Balancementioning

confidence: 99%

“…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.…”

Section: Keeping the Balancementioning

confidence: 99%

Keeping the balance

Dieck

2013

Channels

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The Ca_V1.4 Calcium Channel: More Than Meets the Eye

Cited by 26 publications

References 77 publications

Dysregulation of Ca_v1.4 channels disrupts the maturation of photoreceptor synaptic ribbons in congenital stationary night blindness type 2

Dysregulation of Ca_v1.4 channels disrupts the maturation of photoreceptor synaptic ribbons in congenital stationary night blindness type 2

Calmodulin Interactions withCa_v1 andCa_v2 Voltage‐Gated Calcium ChannelIQDomains

Keeping the balance

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The CaV1.4 Calcium Channel: More Than Meets the Eye

Cited by 26 publications

References 77 publications

Dysregulation of Cav1.4 channels disrupts the maturation of photoreceptor synaptic ribbons in congenital stationary night blindness type 2

Dysregulation of Cav1.4 channels disrupts the maturation of photoreceptor synaptic ribbons in congenital stationary night blindness type 2

Calmodulin Interactions withCav1 andCav2 Voltage‐Gated Calcium ChannelIQDomains

Keeping the balance

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The Ca_V1.4 Calcium Channel: More Than Meets the Eye

Dysregulation of Ca_v1.4 channels disrupts the maturation of photoreceptor synaptic ribbons in congenital stationary night blindness type 2

Dysregulation of Ca_v1.4 channels disrupts the maturation of photoreceptor synaptic ribbons in congenital stationary night blindness type 2

Calmodulin Interactions withCa_v1 andCa_v2 Voltage‐Gated Calcium ChannelIQDomains