Dataset Information

Ca_vβ surface charged residues contribute to the regulation of neuronal calcium channels.

ABSTRACT: Voltage-gated calcium channels are essential regulators of brain function where they support depolarization-induced calcium entry into neurons. They consist of a pore-forming subunit (Ca_vα₁) that requires co-assembly with ancillary subunits to ensure proper functioning of the channel. Among these ancillary subunits, the Ca_vβ plays an essential role in regulating surface expression and gating of the channels. This regulation requires the direct binding of Ca_vβ onto Ca_vα₁ and is mediated by the alpha interacting domain (AID) within the Ca_vα₁ subunit and the α binding pocket (ABP) within the Ca_vβ subunit. However, additional interactions between Ca_vα₁ and Ca_vβ have been proposed. In this study, we analyzed the importance of Ca_vβ₃ surface charged residues in the regulation of Ca_v2.1 channels. Using alanine-scanning mutagenesis combined with electrophysiological recordings we identified several amino acids within the Ca_vβ₃ subunit that contribute to the gating of the channel. These findings add to the notion that additional contacts besides the main AID/ABP interaction may occur to fine-tune the expression and properties of the channel.

SUBMITTER: Tran-Van-Minh A

PROVIDER: S-EPMC8722133 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Cavβ surface charged residues contribute to the regulation of neuronal calcium channels.

Tran-Van-Minh Alexandra A De Waard Michel M Weiss Norbert N

Molecular brain 20220103 1

Voltage-gated calcium channels are essential regulators of brain function where they support depolarization-induced calcium entry into neurons. They consist of a pore-forming subunit (Cavα1) that requires co-assembly with ancillary subunits to ensure proper functioning of the channel. Among these ancillary subunits, the Cavβ plays an essential role in regulating surface expression and gating of the channels. This regulation requires the direct binding of Cav ...[more]

PMID: 34980202

Similar Datasets

Project description:BackgroundMigraine is a painful neurological syndrome characterized by attacks of throbbing headache, of moderate to severe intensity, which is associated with photo- and phono- sensitivity as well as nausea and vomiting. It affects about 15% of the world's population being 2-3 times more prevalent in females. The calcitonin gene-related peptide (CGRP) is a key mediator in the pathophysiology of migraine, and a significant advance in the field has been the development of anti-CGRP therapies. The trigeminal ganglion (TG) is thought to be an important site of action for these drugs. Moreover, experimental migraine can be induced by CGRP injection in the TG. The signaling pathway induced by CGRP in the TG is not fully understood, but studies suggest that voltage-gated calcium channels contribute to CGRP effects relevant to migraine.ObjectiveWe hypothesised that CGRP injection in the TG enhances CaV3.2 T-type calcium channel currents to contribute to the development of periorbital mechanical allodynia.ResultsA Co-Immunoprecipitation assay in tsA-201 cells revealed that CaV3.2 channels form a complex with RAMP-1, a component of the CGRP receptor. Constitutive CGRPR activity was able to inhibit CaV3.2 channels and induce a depolarizing shift in both activation and inactivation curves. Incubation of TG neurons with CGRP increased T-type current density by ~ 3.6 fold, an effect that was not observed in TG neurons from CaV3.2 knockout mice. Incubation of TG neurons with Z944, a pan T-type channel blocker, resulted in an approximately 80% inhibition of T-type currents. In vivo, this treatment abolished the development of periorbital mechanical allodynia induced by CGRP in male and female mice. Likewise, CaV3.2 knockout mice did not develop periorbital mechanical allodynia after intraganglionic CGRP injection. Finally, we demonstrated that the CGRP effect depends on the activation of its canonical GPCR, followed by protein kinase A activation.ConclusionThe present study suggests that CGRP modulates CaV3.2 in the TG, an effect possibly mediated by the canonical CGRP receptor and PKA activation. The increase in T-type currents in the TG may represent a contributing factor for the initiation and maintenance of the headache pain during migraine.

Dataset Information

Ca_vβ surface charged residues contribute to the regulation of neuronal calcium channels.

Publications

Ca<sub>v</sub>β surface charged residues contribute to the regulation of neuronal calcium channels.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets