Protein kinase A modulation of Ca v 1.4 calcium channels

Lingjie Sang; Ivy E. Dick; David T. Yue

doi:10.1038/ncomms12239

Protein kinase A modulation of Ca v 1.4 calcium channels

Lingjie Sang, Ivy E. Dick, David T. Yue

School of Medicine

Research output: Contribution to journal › Article › peer-review

12 Scopus citations

Abstract

The regulation of L-type Ca²⁺ channels by protein kinase A (PKA) represents a crucial element within cardiac, skeletal muscle and neurological systems. Although much work has been done to understand this regulation in cardiac Ca V 1.2 Ca²⁺ channels, relatively little is known about the closely related Ca V 1.4 L-type Ca²⁺ channels, which feature prominently in the visual system. Here we find that Ca V 1.4 channels are indeed modulated by PKA phosphorylation within the inhibitor of Ca²⁺-dependent inactivation (ICDI) motif. Phosphorylation of this region promotes the occupancy of calmodulin on the channel, thus increasing channel open probability (P O) and Ca²⁺-dependent inactivation. Although this interaction seems specific to Ca V_1.4 channels, introduction of ICDI 1.4 to CaV 1.3 or CaV1.2 channels endows these channels with a form of PKA modulation, previously unobserved in heterologous systems. Thus, this mechanism may not only play an important role in the visual system but may be generalizable across the L-type channel family.

Original language	English (US)
Article number	12239
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms12239
State	Published - Jul 26 2016

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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10.1038/ncomms12239

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title = "Protein kinase A modulation of Ca v 1.4 calcium channels",

abstract = "The regulation of L-type Ca2+ channels by protein kinase A (PKA) represents a crucial element within cardiac, skeletal muscle and neurological systems. Although much work has been done to understand this regulation in cardiac Ca V 1.2 Ca2+ channels, relatively little is known about the closely related Ca V 1.4 L-type Ca2+ channels, which feature prominently in the visual system. Here we find that Ca V 1.4 channels are indeed modulated by PKA phosphorylation within the inhibitor of Ca2+-dependent inactivation (ICDI) motif. Phosphorylation of this region promotes the occupancy of calmodulin on the channel, thus increasing channel open probability (P O) and Ca2+-dependent inactivation. Although this interaction seems specific to Ca V1.4 channels, introduction of ICDI 1.4 to CaV 1.3 or CaV1.2 channels endows these channels with a form of PKA modulation, previously unobserved in heterologous systems. Thus, this mechanism may not only play an important role in the visual system but may be generalizable across the L-type channel family.",

author = "Lingjie Sang and Dick, {Ivy E.} and Yue, {David T.}",

note = "Funding Information: This manuscript is dedicated to the memory of our advisor Dr David T. Yue. He was a caring and inspirational mentor who will live in our hearts forever. We thank Dr Nancy Yue, Dr Gordon Tomaselli and Dr King-Wai Yau for generous support and advice. We thank Wanjun Yang for dedicated technical support, Dr Hojjat Bazzazi for the original b2a-Gly8-CaM construct and Dr Rosy Joshi-Mukherjee for the help with the isolation of aGPVMs. We are grateful to Dr Manu Ben-Johny and other members of the Calcium Signals Lab for valuable comments and suggestions. We also thank the JHU SOM Mass Spectrometry and Proteomics Core, Hopkins Digestive Basic and Translational Research Core Center (NIDDK centre grant P30 DK089502) for their support with the mass spectroscopy experiments, and Dr. Robert Cole and Robert O'Meally for generous assistance in writing the manuscript. This work is supported by grants from the NHLBI and NINDS (to D.T.Y.).",

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AU - Sang, Lingjie

AU - Dick, Ivy E.

AU - Yue, David T.

N1 - Funding Information: This manuscript is dedicated to the memory of our advisor Dr David T. Yue. He was a caring and inspirational mentor who will live in our hearts forever. We thank Dr Nancy Yue, Dr Gordon Tomaselli and Dr King-Wai Yau for generous support and advice. We thank Wanjun Yang for dedicated technical support, Dr Hojjat Bazzazi for the original b2a-Gly8-CaM construct and Dr Rosy Joshi-Mukherjee for the help with the isolation of aGPVMs. We are grateful to Dr Manu Ben-Johny and other members of the Calcium Signals Lab for valuable comments and suggestions. We also thank the JHU SOM Mass Spectrometry and Proteomics Core, Hopkins Digestive Basic and Translational Research Core Center (NIDDK centre grant P30 DK089502) for their support with the mass spectroscopy experiments, and Dr. Robert Cole and Robert O'Meally for generous assistance in writing the manuscript. This work is supported by grants from the NHLBI and NINDS (to D.T.Y.).

PY - 2016/7/26

Y1 - 2016/7/26

N2 - The regulation of L-type Ca2+ channels by protein kinase A (PKA) represents a crucial element within cardiac, skeletal muscle and neurological systems. Although much work has been done to understand this regulation in cardiac Ca V 1.2 Ca2+ channels, relatively little is known about the closely related Ca V 1.4 L-type Ca2+ channels, which feature prominently in the visual system. Here we find that Ca V 1.4 channels are indeed modulated by PKA phosphorylation within the inhibitor of Ca2+-dependent inactivation (ICDI) motif. Phosphorylation of this region promotes the occupancy of calmodulin on the channel, thus increasing channel open probability (P O) and Ca2+-dependent inactivation. Although this interaction seems specific to Ca V1.4 channels, introduction of ICDI 1.4 to CaV 1.3 or CaV1.2 channels endows these channels with a form of PKA modulation, previously unobserved in heterologous systems. Thus, this mechanism may not only play an important role in the visual system but may be generalizable across the L-type channel family.

AB - The regulation of L-type Ca2+ channels by protein kinase A (PKA) represents a crucial element within cardiac, skeletal muscle and neurological systems. Although much work has been done to understand this regulation in cardiac Ca V 1.2 Ca2+ channels, relatively little is known about the closely related Ca V 1.4 L-type Ca2+ channels, which feature prominently in the visual system. Here we find that Ca V 1.4 channels are indeed modulated by PKA phosphorylation within the inhibitor of Ca2+-dependent inactivation (ICDI) motif. Phosphorylation of this region promotes the occupancy of calmodulin on the channel, thus increasing channel open probability (P O) and Ca2+-dependent inactivation. Although this interaction seems specific to Ca V1.4 channels, introduction of ICDI 1.4 to CaV 1.3 or CaV1.2 channels endows these channels with a form of PKA modulation, previously unobserved in heterologous systems. Thus, this mechanism may not only play an important role in the visual system but may be generalizable across the L-type channel family.

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Protein kinase A modulation of Ca v 1.4 calcium channels

Abstract

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