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Kicked off the membrane by calcium
Voltage-gated calcium (Cav) channels govern Ca2+ entry into excitable cells, notably neurons, muscles, and secretory cells. These channels have a pore-forming subunit, an auxiliary subunit, and a regulatory β subunit; the electrophysiological and regulatory characteristics of the channel depend on which subunits are present. Kim et al. found that stimulation of G protein–coupled receptors (GPCRs) coupled to Gq (muscarinic acetylcholine receptors and purinergic receptors), which increase intracellular Ca2+, triggered the release of β2e from the membrane, thereby enhancing the inactivation of Cav2.2 channels. Because cellular excitability must be tightly controlled to mediate appropriate physiological responses, maintain organismal homeostasis, and prevent Ca2+ toxicity, Cav channels are subject to complex regulation. Membrane dissociation of β2e by cytosolic Ca2+, which occurred independently of known regulatory mechanisms, adds GPCR signaling to the complexity. β2e and Cav2.2 are abundant in neurons, and these Gq-coupled GPCRs are important in pain signaling and regulation of the cardiovascular system.
Voltage-gated calcium (Cav) channels, which are regulated by membrane potential, cytosolic Ca2+, phosphorylation, and membrane phospholipids, govern Ca2+ entry into excitable cells. Cav channels contain a pore-forming α1 subunit, an auxiliary α2δ subunit, and a regulatory β subunit, each encoded by several genes in mammals. In addition to a domain that interacts with the α1 subunit, β2e and β2a also interact with the cytoplasmic face of the plasma membrane through an electrostatic interaction for β2e and posttranslational acylation for β2a. We found that an increase in cytosolic Ca2+ promoted the release of β2e from the membrane without requiring substantial depletion of the anionic phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2) from the plasma membrane. Experiments with liposomes indicated that Ca2+ disrupted the interaction of the β2e amino-terminal peptide with membranes containing PIP2. Ca2+ binding to calmodulin (CaM) leads to CaM-mediated inactivation of Cav currents. Although Cav2.2 coexpressed with β2a required Ca2+-dependent activation of CaM for Ca2+-mediated reduction in channel activity, Cav2.2 coexpressed with β2e exhibited Ca2+-dependent inactivation of the channel even in the presence of Ca2+-insensitive CaM. Inducible depletion of PIP2 reduced Cav2.2 currents, and in cells coexpressing β2e, but not a form that lacks the polybasic region, increased intracellular Ca2+ further reduced Cav2.2 currents. Many hormone- or neurotransmitter-activated receptors stimulate PIP2 hydrolysis and increase cytosolic Ca2+; thus, our findings suggest that β2e may integrate such receptor-mediated signals to limit Cav activity.