Biology subjects

De la Rosa Vazquez, J.

Publications and source records attributed to De la Rosa Vazquez, J..

2 recordsLinked to original sources

bioRxiv2026

CACNA2D4 variants are associated with exertional heat stroke susceptibility

Exertional Heat Stroke (EHS) is a life-threatening disease defined by severe hyperthermia and sudden neurological dysfunction in healthy individuals exposed to intense physical exercise. As is the case with some forms of malignant hyperthermia, mutations in genes involved in skeletal muscle contraction could predispose some patients to EHS. However, the genetic basis of EHS remains poorly documented. Here we identify EHS-associated variants in the CACNA2D4 gene encoding the Cav Ca2+ channel subunit, 2{delta}4, and describe their impact in heterologous expression systems and a knock-in mutant mouse strain heterozygous for the S299R variant (S299R+/-). In transfected cells, each CACNA2D4 variant, including S299R, affected the trafficking and function of 2{delta}4 and its regulation of the Cav1.1 channel. S299R+/-mice showed EHS-like crisis with signs of rhabdomyolysis and an elevation in core body temperature when submitted to an intense exercise protocol. We show that a CACNA2D4 transcript is expressed in mouse skeletal muscle and that the presence of the S299R variant in 2{delta}4 induces a modification in the calcium flux triggered by muscle cell depolarization. Altogether, our data reveal an unexpected connection between CACNA2D4 gene variants and pathophysiological alterations in skeletal muscle Ca2+ signaling that may increase EHS susceptibility.

genetics↗

bioRxiv2024

Complex regulation of Cav2.2 N-type Ca2+ channels by Ca2+ and G-proteins

G-protein coupled receptors inhibit Cav2.2 N-type Ca2+ channels by a fast, voltage-dependent pathway mediated by Gi/ G{beta}{gamma} and a slow, voltage-independent pathway mediated by Gq-dependent reductions in phosphatidylinositol 4,5-bisphosphate (PIP2) or increases in arachidonic acid. Studies of these forms of regulation generally employ Ba2+ as the permeant ion, despite that Ca2+ -dependent pathways may impinge upon G-protein modulation. To address this possibility, we compared tonic G-protein inhibition of currents carried by Ba2+ (IBa) and Ca2+ (ICa) in HEK293T cells transfected with Cav2.2. Both IBa and ICa exhibited voltage-dependent facilitation (VDF), consistent with G{beta}{gamma} unbinding from the channel. Compared to that for IBa, VDF of ICawas less sensitive to an inhibitor of G proteins (GDP-{beta}-S) and an inhibitor of G{beta}{gamma} (C-terminal construct of G-protein coupled receptor kinase 2). While insensitive to high intracellular Ca2+ buffering, VDF of ICa that remained in GDP-{beta}-S was blunted by reductions in PIP2. We propose that when G-proteins are inhibited, Ca2+ influx through Cav2.2 promotes a form of VDF that involves PIP2. Our results highlight the complexity whereby Cav2.2 channels integrate G-protein signaling pathways, which may enrich the information encoding potential of chemical synapses in the nervous system.

neuroscience↗