Voltage-dependent calcium channel

Available evidence suggests that a single unifying mechanism does not exist but rather that various vasodilators may act at different places in the series of processes that couple excitation of vascular smooth muscle cells with contraction. For example, the vasodilators known as calcium channel antagonists block or limit the entry of calcium through voltage-dependent channels in the membrane of vascular smooth muscle cells. In this way, the calcium channel blockers limit the amount of free intracellular calcium available to interact with smooth muscle contractile proteins (see Chapter 14). 

Serum withdrawal affects the expression of plasma membrane calcium channels in diverse ways. Voltage-dependent calcium channels have their expression increased in the absence of serum in the culture medium (Ihara, et al., 2002, Kushmerick, et al., 2001, Patel, et al., 2005), whereas non voltage-dependent channels are down regulated (Golovina, 1999, Golovina, et al., 2001, Sweeney, et al., 2002, Yu, et al., 2004, Yu, et al., 2003). 

Depolarization of vascular smooth muscle activates the L-type calcium channels, which results in increased cytosolic concentrations of calcium and hence increased tone. Calcium channel blockers (e.g., verapamil and diltiazem) block the influx of calcium through the L-type voltage-dependent channels located on vascular smooth muscle and cardiac muscle cells as well as cardiac nodal cells. Therefore, they are used in the treatment of angina, hypertension, and certain arrhythmias. 

Smooth muscle exhibits very diverse behaviors depending on which control mechanisms are present. Vascular smooth muscle, for example, lacks fast voltage-dependent Na+ or Ca + channels and so does not have action potentials or Ca + spikes. It has slow voltage-dependent Ca + channels that admit calcium in a graded fashion in response to fluctuations in membrane potential induced by humoral or transmitter effects on membrane ion conductances, and it has several membrane receptor-initiated second-messenger cascades that control Ca " " entry and Ca + release from its limited SR, and which moderate the effectiveness of Ca +. Vascular smooth muscle contraction is thus tonic rather than phasic, and is very dependent on extracellular Ca + therefore Ca + channel blockers effectively inhibit contraction. In contrast, gut smooth muscle does have fast voltage-dependent channels sufficient to produce action potentials and more SR than vascular smooth muscle, and also has gap junctions through which ion fluxes can occur. It also has receptor-mediated Ca +... 

Under conditions of the resting cell, all these voltage-dependent channels are closed. Activated by depolarization, they allow huge amounts of calcium to enter the cell. These channels are controlled by complex regulation systems involving different neurotransmitters. 

The observations that cholinergic agonists elevate IP3 levels in gastric celb and that IP3 releases calcium from internal stores in permeabilized parietal cells provide evidence that the initial peak response of [Ca], is due to activation of IP3 receptor-activated Caj. channels. This is consistent also with the finding that the cloned M3 receptor mediates phosphoinositide hydrolysis. The agonist-dependent formation of IP3 is likely due to activation of phospholipase C. There are various isoforms of this enzyme. The exact mechanism for calcium influx that results in the steady-state elevation of Ca, remains unidentified. The influx pathway is not a voltage-dependent channel, because it is not blocked by dihydropyridine-type channel blockers. 

Diltiazem inhibits calcium influx via voltage-operated channels and therefore decreases intracellular calcium ion. This decreases smooth muscle tone. Diltiazem dilates both large and small arteries and also inhibits a-adrenoceptor activated calcium influx. It differs from verapamil and nifedipine by its use dependence. In order for the blockade to occur, the channels must be in the activated state. Diltiazem has no significant affinity for calmodulin. The side effects are headache, edema, and dizziness. 

Antidiabetic Drugs other than Insulin. Figure 1 Sulphonylureas stimulate insulin release by pancreatic (3-cells. They bind to the sulphonylurea receptor (SUR-1), which closes Kir6.2 (ATP-sensitive) potassium channels. This promotes depolarisation, voltage-dependent calcium influx, and activation of calcium-sensitive proteins that control exocytotic release of insulin. 

Stimulation of mAChRs also results in the activation or inhibition of a large number of ion channels [5]. For example, stimulation of Mi receptors leads to the suppression of the so-called M current, a voltage-dependent Recurrent found in various neuronal tissues. M2 receptors, on the other hand, mediate the opening of cardiac Ikcacii) channels, and both M2 and M4 receptors are linked to the inhibition of voltage-sensitive calcium channels [5]. 

Voltage-dependent Ca2+ channels are a family of multi-subunit complexes of five proteins responding to membrane depolarisation with channel opening allowing the influx of calcium into a cell. Voltage-dependent calcium channels are subdivided into three subfamilies the HVA DHP-sensitive L-type calcium channels, the HVA DHP-insensitive calcium channels and the LVA T-type calcium channels [2]. 

Voltage-dependent Ca2 Channels. Figure 1 Structure, identity and blockers of calcium channel subunits. 

Voltage-dependent Ca2+ Channels. Figure 2 Subunit composition of a HVA calcium channel. The selectivity filter of the channel is created by four glutamates (E). 

More recent analysis of tissue specific gene deletions showed that the Cav1.2 channel is involved in a wide variety of function including hippocampal learning, insulin secretion, intestine and bladder motility. Further analysis will be required to unravel the functional significance of voltage-dependent calcium channels for specific cellular functions. 

Hofmann F, Lacinova L, Klugbauer N (1999) Voltage-dependent calcium channels from structure to function. Rev Physiol Biochem Pharmacol 139 33-87... 

Carmignoto G, Pasti L, Pozzan T (1998) On the role of voltage-dependent calcium channels in calcium signaling of astrocytes in situ. J Neurosci 18 4637-4645 Cartier L, Hartley O, Dubois-Dauphin M, Krause KH (2005) Chemokine receptors in the central nervous system role in brain inflammation and neurodegenerative diseases. Brain Res Brain Res Rev 48 16 2... 

Brown, DA (2000) The acid test for resting potassium channels. Curr. Biol. 10 R456-R459. Dolphin, AC (1998) Mechanisms of modulation of voltage-dependent calcium channels by G proteins. J. Physiol. 506 3-11. 

Ikeda, S. R. and Dunlap, K., Voltage-dependent modulation of N-type calcium channels role of G-protein subunits, Adv. Second Messenger Phosphoprotein Res., 33, 131-151, 1999. 

Ionized calcium (Ca2+) is the most common signal transduction element in cells [66], Excitable cells, like neurons, contain voltage-dependent Ca2+ channels, which enable these cells to drastically increase cytosolic calcium levels. Rapid fluctuations in presynaptic... 

Increases in the concentration of calcium in the cytosol provides a signal that can initiate muscle contraction, vision, and other signaling pathways. The response depends on the cell type. In muscle, a transient rise in the cytosolic calcium levels (from opening calcium channels in the sarcoplasmic reticulum) causes contraction. This signaling in contraction is a direct consequence of electrical activation of the voltage-gated channel. 

Ca2+ can enter cells via voltage- or ligand-dependent channels and by capacitative entry. These three fundamental mechanisms of regulated calcium ion entry across the plasma membrane involve, respectively, voltage-dependent Ca2+ channels, ligand-gated Ca2+ channels and capacitative Ca2+ entry associated with phospholipase C-coupled receptors. 

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