Regulation of microdomain voltage-gated L-type calcium channels in cardiac health and disease

Abstract The junctophilin family of proteins tether together plasma membrane (PM) and endoplasmic reticulum (ER) membranes, and couple PM- and ER-localized calcium channels. Understanding in vivo functions of junctophilins is of great interest for dissecting the physiological roles of ER-PM contact sites. Here, we show that the sole C. elegans junctophilin JPH-1 localizes to discrete membrane contact sites in neurons and muscles and has important tissue-specific functions. jph-1 null mutants display slow growth and development due to weaker contraction of pharyngeal muscles, leading to reduced feeding. In the body wall muscle, JPH-1 co-localizes with the PM-localized EGL-19 voltage-gated calcium channel and ER-localized UNC-68/RyR calcium channel, and is required for animal movement. In neurons, JPH-1 co-localizes with the membrane contact site protein Extended-SYnaptoTagmin 2 (ESYT-2) in soma, and is present near presynaptic release sites. Interestingly, jph-1 and esyt-2 null mutants display mutual suppression in their response to aldicarb, suggesting that JPH-1 and ESYT-2 have antagonistic roles in neuromuscular synaptic transmission. Additionally, we find an unexpected cell non-autonomous effect of jph-1 in axon regrowth after injury. Genetic double mutant analysis suggests that jph-1 functions in overlapping pathways with two PM-localized voltage-gated calcium channels, egl-19 and unc-2, and unc-68/RyR for animal health and development. Finally, we show that jph-1 regulates the colocalization of EGL-19 and UNC-68 and that unc-68/RyR is required for JPH-1 localization to ER-PM puncta. Our data demonstrate important roles for junctophilin in cellular physiology, and also provide insights into how junctophilin functions together with other calcium channels in vivo.

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Cross your heart? Collagen cross-links in cardiac health and disease

Cellular Signalling ◽

10.1016/j.cellsig.2020.109889 ◽

2021 ◽

Vol 79 ◽

pp. 109889

Author(s):

Lily S. Neff ◽

Amy D. Bradshaw

Keyword(s):

Cardiac Health ◽

Health And Disease ◽

Cross Links

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Presynaptic Paraneoplastic Disorders of the Neuromuscular Junction: An Update

Brain Sciences ◽

10.3390/brainsci11081035 ◽

2021 ◽

Vol 11 (8) ◽

pp. 1035

Author(s):

Maria Pia Giannoccaro ◽

Patrizia Avoni ◽

Rocco Liguori

Keyword(s):

Potassium Channels ◽

Neuromuscular Junction ◽

Calcium Channels ◽

Myasthenia Gravis ◽

Neuromuscular Transmission ◽

Voltage Gated ◽

Voltage Gated Calcium Channels ◽

Immune Mediated ◽

Recent Developments ◽

Myasthenic Syndrome

The neuromuscular junction (NMJ) is the target of a variety of immune-mediated disorders, usually classified as presynaptic and postsynaptic, according to the site of the antigenic target and consequently of the neuromuscular transmission alteration. Although less common than the classical autoimmune postsynaptic myasthenia gravis, presynaptic disorders are important to recognize due to the frequent association with cancer. Lambert Eaton myasthenic syndrome is due to a presynaptic failure to release acetylcholine, caused by antibodies to the presynaptic voltage-gated calcium channels. Acquired neuromyotonia is a condition characterized by nerve hyperexcitability often due to the presence of antibodies against proteins associated with voltage-gated potassium channels. This review will focus on the recent developments in the autoimmune presynaptic disorders of the NMJ.

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Voltage-gated calcium channel blockers for psychiatric disorders: genomic reappraisal

The British Journal of Psychiatry ◽

10.1192/bjp.2019.157 ◽

2019 ◽

Vol 216 (5) ◽

pp. 250-253 ◽

Cited By ~ 8

Author(s):

Paul J. Harrison ◽

Elizabeth M. Tunbridge ◽

Annette C. Dolphin ◽

Jeremy Hall

Keyword(s):

Calcium Channels ◽

Calcium Channel ◽

Psychiatric Disorders ◽

Calcium Channel Blockers ◽

Channel Blockers ◽

Risk Genes ◽

Voltage Gated ◽

Voltage Gated Calcium Channels ◽

Voltage Gated Calcium Channel ◽

Second Use

SummaryWe reappraise the psychiatric potential of calcium channel blockers (CCBs). First, voltage-gated calcium channels are risk genes for several disorders. Second, use of CCBs is associated with altered psychiatric risks and outcomes. Third, research shows there is an opportunity for brain-selective CCBs, which are better suited to psychiatric indications.

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