Research Area

Calcium Channel


Introduction of calcium channel

Calcium is the oldest and most widely used signaling substance in the cell and is involved in the regulation of almost all biological functions of the body, such as cardiac and muscle contraction, neuronal transmission, learning and memory, embryogenesis and development, cell proliferation and apoptosis, cell division and differentiation, cell energy metabolism, protein phosphorylation and dephosphorylation modification, and gene expression and regulation. The cytoplasmic free calcium ion concentration of mammalian cells is generally controlled at 100-200 nmol/L. The steep but tightly controlled concentration gradient of calcium ions between the cell membrane and the cytoplasm and organelles is maintained and dynamically regulated according to the needs of the cells. It relies on a variety of ion channels, ion pumps, and transporters to work together. Although different cells have different specific mechanisms, the molecules involved in calcium channel is including cell membranes and organelle membrane ion channels (mediating calcium ions into the cytoplasm), transporters of cell membranes and organelle membranes (including primary active transport and secondary transport), cytoplasmic and organelle calcium buffer protein (combined storage of calcium ions), etc. Any abnormality in the links may cause instability of calcium homeostasis and cause disease. Elucidation of the regulation mechanism of calcium channel reveals one of the basic links of calcium homeostasis and the regulation of life processes.

The family member of calcium channel and their structures respectively

The calcium ion channel is a protein complex that causes calcium ions to flow between the inside and outside of the cell as well as between the organelle and the cytoplasm. The sources of intracellular calcium are two kinds of extracellular calcium influx and intracellular calcium stores. The entry of extracellular calcium into the cell can be achieved by the following three receptor channel pathways: Cav channel, receptor-gated calcium channel, calcium reservoir controlling calcium channel, and intracellular calcium store release is mainly through 4 receptor channel pathways, ie. IP3R channel, ryanodine receptor channel, nicotinic acid adenine dinucleotide phosphate (NAADP) receptor channel, and mitochondrial receptor channel. In addition, the calcium outflow in the endoplasmic reticulum caused by an increase in intracellular calcium ion concentration is called Ca2+ induced Ca2+ release. The Cav channel on the islet β cell membrane and the IP3R channel, RYR channel, and NAADP receptor channel on the intracellular calcium library are the four major receptor channels involved in the insulin secretion process. Islet β extracellular calcium influx is mainly through the Cav channel. According to electrophysiological characteristics, Cav channels can be divided into L, P/Q, N, R and T types, of which L-type Cav channels play a decisive role in triggering insulin secretion. The Cav channel usually consists of 4 or 5 of the α1, α2δ, β, and γ subunits. The α1 subunit is the main subunit of the Cav channel, which constitutes the transport channel of calcium ions. Other subunits do not participate in the formation of the Cav channel, but regulate the opening of the α1 subunit channel and are therefore called auxiliary subunits. Among them, the α2δ subunit is linked by an extracellular glycosylated α2 subunit and a hydrophobic transmembrane δ subunit through a disulfide bond. In addition, the α2 subunit has a binding site for a calcium ion antagonist, and the dihydropyridine calcium ion antagonist mainly functions by binding to the α2 subunit. IP3R is a glycoprotein with a relative molecular mass of approximately 240000 to 300000. IP3R is divided into I-V type, of which type I-III is expressed on islet β cells, especially type III is most abundant. IP3R is distributed in the endoplasmic reticulum of beta cells, and studies have confirmed that IP3R is also present on insulin secretory granules. IP3R has the property of binding to inositol triphosphate (IP3) and transporting calcium ions. IP3R is formed by non-covalent association of homotetramers, and each subunit can bind one molecule of IP3. IP3R can be divided into three parts: IP3 binding zone, function regulation zone and calcium ion channel zone. The calcium channel region is the basis for the formation of the IP3R tetramer structure, so the calcium channel region is very important for the structure of IP3R. The RYR channel is a protein of 45,000 amino acids expressed on the endoplasmic reticulum and sarcoplasmic reticulum with a relative molecular mass of 565,000. Depending on the coding gene, RYR is divided into three subtypes: RYR1, RYR2 and RYR3. There are mainly RYR2 channels on the endoplasmic reticulum of islet β cells.

Calcium channel-related disease and the mechanism of the calcium channel working in these disease

The Ca2+ channel is a transmembrane multi-subunit protein, and the voltage-gated Ca2+ channel is generally classified into L-type (Cav1), P/Q-type (Cav2.1), N-type (Cav2.2), and R-type (Cav2. 3) and T-type (Cav3) and other subtypes, distributed in neurons, myocardium and other parts, and involved in neurotransmitter release and myocardial action potential. The study found that anti-depressants stimulate gynogenesis in hippocampus involving G-protein coupled receptors and voltage-dependent calcium channels. Clinical evidence suggests that L-type calcium channel blockers can treat bipolar disorder, schizophrenia, and a series of neuropsychiatric diseases such as depression. Cav1 and Cav3 molecules are associated with rodent emotions (anxiety, depression), social behavior, and cognition. Studies have found that blocking calcium channels with selective P-type and P/Q-type calcium channel blocker ω-viral IVA can alter the efficiency of synaptic transmission, demonstrating that P-type and P/Q-type calcium channels are involved in hippocampal nerves. Studies have used whole-cell patch-clamp recording and Ca2+ imaging techniques to study the mechanism of long-term inhibition in pyramidal neurons in the hippocampal CA1 region of acute brain slices and found that N-type Ca2+ channels are involved in hippocampal pyramidal neurons and synaptic plasticity. Islet beta cells are very sensitive to changes in extracellular glucose concentration. When the extracellular glucose concentration is elevated, glucose is taken up into the beta cells through the glucose carrier on the beta cell membrane. Through the Krebs cycle, the intracellular ATP/ADP ratio is increased. The ATP-sensitive potassium channel is closed, the K+ outflow is reduced, the β cell membrane is depolarized, and the Cav channel is opened, and the external calcium influx increases the intracellular calcium ion concentration, triggering the exocytosis and β on the insulin vesicle membrane. The actin in the cell membrane acts to fuse the insulin vesicle membrane with the β cell membrane to form a membrane fusion pore, and then the insulin in the vesicle is released to the extracellular space through the fusion pore to realize the exocytosis process of the β cell. A variety of drugs such as 2, 2-dithiodipyridine, thiopental, and interleukin 6 can induce or increase the effect of glucose-stimulated insulin secretion, all of which involve the release of calcium ions involved in the IP3R channel. As the largest calcium reservoir in the cell, the endoplasmic reticulum has IP3R and RYR, which plays an important role in insulin secretion; in the rat insulinoma cell line INS1, insulin secretion can be inhibited by emptying the IP3-mediated calcium pool. All of the above experiments confirmed that the IP3R channel is involved in the insulin secretion process. RYR is involved in glucose and incretin secreted peptide-mediated β-cell insulin secretion, and the state of diabetes is associated with decreased expression of RYR in beta cells. In addition to being expressed on the endoplasmic reticulum of pancreatic islet β cells, RYR is also present in beta cell insulin secretory vesicles. Local CICR may be involved in the triggering process of insulin vesicle exocytosis; insulin secretion is triggered by an increase in intracellular calcium concentration in islet β cells, which leads to activation of calmodulin-dependent protein kinase, which phosphorylates RYR2 and produces endoplasmic reticulum calcium outflow. This CICR process is glucose concentration dependent. Phosphorylation of RYR2 is thought to be a mechanism that causes the release of intracellular calcium stores to mediate insulin secretion. Dixit et al. knocked the RYR2 channel mutant into mice, mimicking RYR2-type channel phosphorylation, resulting in increased RYR2-mediated calcium efflux, which in turn produced basal hyperinsulinemia. Both experiments demonstrate that RYR is involved in the insulin secretion process. The NAADP receptor channel is also involved in glucose and incretin secreted peptide-mediated beta cell insulin secretion. Studies have shown that incretin secreted peptides, such as glucagon-like peptide 1, induce beta-cell calcium release. Primary calcium release is mediated by NAADP, and secondary calcium release is mediated through cyclic adenosine diphosphate ribose polymerase, which ultimately completes the insulin via the guanine nucleotide exchange pathway regulated by protein kinase A and cyclic adenosine monophosphate secretion. In addition, the study also confirmed that NAADP not only plays a role in the glucagon-like peptide-1-induced calcium release, but also acts as a calcium signal. Studies have confirmed that both TPC1 and TPC2 are involved in NAADP-induced calcium release, but CICR is closely related to TPC2. In contrast, expression of TPC3 inhibited NAADP-induced calcium release. Ultimately, the expression of TPC affects the structure and dynamics of endosomes, making NAADP an important player in regulating vesicle trafficking.

Reference:

  1. Nimmrich V, Eckert A. Calcium channel blockers and dementia. British Journal of Pharmacology. 2013, 169(6):1203-1210.
  2. Simms B A, Zamponi G W. Neuronal voltage-gated calcium channels: structure, function, and dysfunction. Neuron. 2014, 82(1):24-45.
  3. Hofmann F, Flockerzi V, Kahl S, et al. L-type CaV1.2 calcium channels: from in vitro findings to in vivo function. Physiological Reviews. 2014, 94(1):303-326.
  4. Dolphin A C. Calcium channel auxiliary α2δ and β subunits: trafficking and one step beyond. Nature Reviews Neuroscience. 2012, 13(8):542.
  5. Dong H, Klein M L, Fiorin G. Counterion-assisted cation transport in a biological calcium channel.Journal of Physical Chemistry B. 2014, 118(32):9668.

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