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Voltage-gated calcium channels: How to activate calcium influx via voltage?
Voltage-gated calcium channels (VGCCs) are a type of ion channels that exist on the membranes of excitable cells (such as muscles, nerve cells, and glial cells). These channels are highly permeable to calcium ions (Ca2+), approximately 1,000 times more permeable than sodium ions (Na+
Calculating the concentration of intracellular calcium ions shows that the calcium concentration outside the cell is usually thousands of times higher than inside the cell, allowing the cell to rapidly influx calcium when needed. When VGCCs are activated, calcium influx may lead to different physiological responses that depend on the cell type. For example, the influx of calcium can promote nerve excitation, stimulate muscle contraction, upregulate gene expression, or release hormones and neurotransmitters. VGCCs are complexes composed of multiple different subunits, including α1, α2δ, β1-4, and γ. The α1 subunit forms the channel's current-conducting pore, while other related subunits help regulate the channel's switching behavior. The α1 subunit is the most basic component of VGCCs, weighing approximately 190 kDa. It contains four homologous I-IV domains, each containing six transmembrane α-helices. In the laboratory, researchers can distinguish different types of high-voltage-gated calcium channels (HVGCCs) based on the channels' physiological roles or inhibitory responses to specific toxins. Such as N-type channel, R-type channel, P/Q-type channel and L-type channel, etc. L-type calcium channels open when a smooth muscle cell depolarizes, which can be caused by stretching of the cell, binding of ligands to G protein-coupled receptors, or stimulation of the autonomic nervous system. The opening of L-type calcium channels leads to the outflow of calcium into the cell, and then calcium ions bind to calmodulin, inducing smooth muscle contraction. In heart and skeletal muscle, the opening of L-type calcium channels is associated with mechanical coupling of calcium release channels, a phenomenon called calcium-induced calcium release (CICR). VGCCs are clinically associated with a variety of diseases. For example, its antibodies are common in Lambert-Eaton myasthenic syndrome and have been implicated in the regression of certain types of tumors. In addition, mutations in VGCCs have been linked to heart disease and mental disorders such as bipolar disorder and schizophrenia. Recent studies have shown that the function and regulation of VGCCs are critical to the life activities of cells. Since these channels further affect the biological behavior of cells, finding new targets to regulate the activities of these channels may become one of the future therapeutic strategies. As the understanding of VGCCs deepens, researchers must consider the role of these channels in physiological and pathological processes. What kind of inspiration can it bring to the prevention and treatment of diseases in the future?
Channel structure
Physiological functions
Clinical importance
