scholarly journals Different α2δ Accessory Subunits Regulate Distinctly Different Aspects of Calcium Channel Function in the Same Drosophila Neurons

2019 ◽  
Author(s):  
Laurin Heinrich ◽  
Stefanie Ryglewski
Keyword(s):  
Calcium Channels ◽  
Calcium Channel ◽  
Intracellular Signaling ◽  
Brain Diseases ◽  
Voltage Gated ◽  
Channel Function ◽  
Voltage Gated Calcium Channels ◽  
Accessory Subunits ◽  
Neuronal Compartments

AbstractVoltage gated calcium channels (VGCCs) regulate neuronal excitability and translate activity into calcium dependent intracellular signaling. The pore forming α1 subunit of high voltage activated (HVA) VGCCs operates not in isolation but associates with α2δ accessory subunits. α2δ subunits can affect calcium channel biophysical properties, surfacing, localization and transport, but their in vivo functions are incompletely understood. In vertebrates, it is largely unknown whether different combinations of the four α2δ and the 7 α1 subunits mediate different or partially redundant functions or whether different α1/α2δ combinations regulate different aspects of VGCC function. This study capitalizes on the relatively simpler situation in the Drosophila genetic model that contains only two genes for HVA calcium channels, one Cav1 homolog and one Cav2 homolog, both with well-described functions in different compartments of identified motoneurons. We find that both dα2δ1 and dα2δ3 (stj) are broadly but differently expressed in the nervous system. Both are expressed in motoneurons, but with differential subcellular localization. Functional analysis reveals that dα2δ3 is required for normal Cav1 and Cav2 current amplitudes and for correct Cav2 channel function in all neuronal compartments, axon terminal, axon, and somatodendritic domain. By contrast, dα2δ1 does not affect Cav1 or Cav2 current amplitudes or presynaptic function, but it is required for correct Cav2 channel allocation to the axonal versus the dendritic domain. Therefore, different α2δ subunits are required in the same neurons to precisely regulate distinctly different functions of HVA calcium channels, which is in accord with specific α2δ mutations causing different brain diseases.Significance StatementCalcium influx through the pore forming α1-subunit of voltage gated calcium channels serves essential neuronal functions, such as synaptic vesicle release, control of action potential shape and frequencies, synaptic input computations, and transcriptional control. Localization and function of α1-calcium channel subunits depend on interactions with α2δ accessory subunits. Here we present in vivo analysis of Drosophila motoneurons revealing that different α2δ subunits independently regulate distinctly different aspects of calcium channel function in the same neuron, such as current amplitude and dendritic versus axonal channel localization. Our findings start unraveling how different α1/α2δ combinations regulate functional calcium channel diversity in different sub-neuronal compartments, and may provide an entry point toward understanding how mutations of different α2δ genes underlie brain diseases.

scholarly journals Caenorhabditis elegans Junctophilin has tissue-specific functions and regulates neurotransmission with extended-synaptotagmin

Genetics ◽  
2021 ◽  
Author(s):  
Christopher A Piggott ◽  
Zilu Wu ◽  
Stephen Nurrish ◽  
Suhong Xu ◽  
Joshua M Kaplan ◽  
...  
Keyword(s):  
Calcium Channels ◽  
Calcium Channel ◽  
Tissue Specific ◽  
Voltage Gated ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Pharyngeal Muscles ◽  
Membrane Contact ◽  
Null Mutants

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.

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

2019 ◽  
Vol 216 (5) ◽  
pp. 250-253 ◽  
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.

Modeling ion permeation through a bacterial voltage-gated calcium channel CaVAb using molecular dynamics simulations

2017 ◽  
Vol 13 (1) ◽  
pp. 208-214 ◽  
Author(s):  
Jamal Adiban ◽  
Yousef Jamali ◽  
Hashem Rafii-Tabar
Keyword(s):  
Molecular Dynamics ◽  
Calcium Channels ◽  
Calcium Channel ◽  
Molecular Dynamics Simulations ◽  
Selectivity Filter ◽  
Ion Permeation ◽  
Voltage Gated ◽  
Voltage Gated Calcium Channels ◽  
Voltage Gated Calcium Channel ◽  
Dynamics Simulations

Ca2+ion binds tightly to the center of the selectivity filter of voltage-gated calcium channels.

scholarly journals A new homozygous CACNB2 mutation has functional relevance and supports a role for calcium channels in autism spectrum disorder

2019 ◽  
Author(s):  
Claudio Graziano ◽  
Patrick Despang ◽  
Flavia Palombo ◽  
Giulia Severi ◽  
Annio Posar ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Calcium Channels ◽  
Calcium Channel ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Site Directed Mutagenesis ◽  
Global Developmental Delay ◽  
Whole Cell ◽  
Voltage Gated ◽  
Voltage Gated Calcium Channels

Abstract BackgroundDiagnostic yield in patients with autism spectrum disorder (ASD) has improved over the last years, thanks to the introduction of whole genome arrays and next generation sequencing, but etiology is still unknown for the majority of cases. Among distinct cellular pathways, evidence implicating dysregulation of cellular calcium homeostasis in ASD pathogenesis has been accumulating, and specific mutations in voltage-gated calcium channels found in patients with autism were shown to be functionally relevant.MethodsWhole exome sequencing and Sanger sequencing were performed to identify and confirm variants in a girl with ASD, global developmental delay and precocious puberty, born of first-degree cousins. Site-directed mutagenesis was used to generate a human CaVβ2d calcium channel subunit carrying a CACNB2 mutation. Whole-cell patch-clamp recordings were performed to reveal functional effects of mutant CaVβ2d on Ba2+-currents mediated by L-type (CaV1.2) calcium channels in transiently transfected HEK-293 cells.ResultsIn an ASD patient, we identified a rare homozygous variant (p.Arg70Cys) in the CACNB2 gene coding for the auxiliary CaVβ2subunit of voltage-gated calcium channels. In a recombinant system, the CaVβ2 variant, which was not previously associated to ASD, was found to alter CaV1.2 calcium channel function by significantly affecting activation and inactivation of whole-cell Ba2+-currents.LimitationsAlthough the evidence of CACNB2 involvement in ASD is slowly accumulating, the number of reported patients is very limited. Deep clinical phenotyping and functional studies in larger sets of subjects will be instrumental to fully understand the penetrance and outcome of CACNB2 variants.ConclusionsThe p.Arg70Cys variant in CACNB2 shows functional consequences similar to other ASD-associated CaVβ2 mutations. These results support the idea of CACNB2 variations contributing to the development of ASD and hint to a rare form of Mendelian recessive autism with possible specific comorbidities.

Voltage-gated calcium channels: Determinants of channel function and modulation by inorganic cations

2015 ◽  
Vol 129 ◽  
pp. 1-36 ◽  
Author(s):  
Felix Neumaier ◽  
Maxine Dibué-Adjei ◽  
Jürgen Hescheler ◽  
Toni Schneider
Keyword(s):  
Calcium Channels ◽  
Voltage Gated ◽  
Inorganic Cations ◽  
Channel Function ◽  
Voltage Gated Calcium Channels

Dependency of hypoxic chemotransduction in cat carotid body on voltage-gated calcium channels

1991 ◽  
Vol 71 (3) ◽  
pp. 1062-1069 ◽  
Author(s):  
M. Shirahata ◽  
R. S. Fitzgerald
Keyword(s):  
Calcium Channels ◽  
Calcium Channel ◽  
Intracellular Calcium ◽  
Carotid Body ◽  
Calcium Ions ◽  
Extracellular Calcium ◽  
Bay K 8644 ◽  
Voltage Gated ◽  
Voltage Gated Calcium Channels ◽  
Selective Perfusion

The hypothesis that the entry of extracellular calcium ions into some compartment, quite possibly the type I cells, through voltage-gated calcium channels (VGCC) is essential for hypoxic chemotransduction in the cat carotid body was tested using an in situ perfusion technique. The neural output of the carotid body of anesthetized, paralyzed, and artificially ventilated cats in response to perfusions with Krebs-Ringer bicarbonate solution (KRB), calcium-free KRB, KRB containing calcium channel blockers, or KRB containing BAY K 8644 was recorded. Selective perfusion of the carotid body with hypoxic calcium-free KRB significantly decreased carotid chemoreceptor activity, suggesting that extracellular calcium is essential for hypoxic chemotransduction. Selective perfusion of the carotid body with hypoxic KRB containing verapamil (10–100 microM), diltiazem (10–100 microM), or nifedipine (10–100 microM) dose dependently attenuated the increase in chemoreceptor activity produced by hypoxia, suggesting that VGCC need to be activated for hypoxic chemotransduction. The carotid body response to hyperoxic KRB containing the calcium channel agonist BAY K 8644 (10 microM) was 267 +/- 87% of hyperoxic control KRB, suggesting that an enhanced influx of calcium ions through VGCC stimulates carotid chemoreceptor activity. Selective perfusion of the carotid body with severely hypoxic KRB containing BAY K 8644 did not increase chemoreceptor activity above that produced by severe hypoxia alone. This suggests that severe hypoxia increases intracellular calcium in some compartment of the carotid body to achieve stimulatory maximum response and that further increase in intracellular calcium does not produce further elevation of neural activity.(ABSTRACT TRUNCATED AT 250 WORDS)

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