Ca2+ channels L-type

Quinidine, the classical class IA drug, binds to the open state oftheNa+ channel, and prolongs the action potential by block of the delayed rectifier-. In higher concentrations, L-type Ca2+ channels are inhibited. Quinidine exerts antimuscarinic effects, thereby accelerating AV-nodal... 

Verapamil is a phenylalkylamine which blocks L-type Ca2+ channels in a use-dependent manner. The drug binds to the inactivated state of the channel. Diltiazem is a benzothiazepine derivative with a profile of action most similar to that of verapamil. 

This synopsis refers only to actions demonstrated within or close to therapeutic concentrations of drugs. Abbreviations (+) to (+++) weak to strong efficacy, (-) no efficacy, ( ) not investigated. HVA high threshold Ca2 channels, T T-type Ca2+ channels, L L-type Ca2+ channels, iNap persistent sodium current, DR delayed rectifier K channels, KCNQ KCNQ subtypes of K+ channels. 

Sorcin (soluble resistance-related calcium binding protein) was isolated from multidrug-resistant cells and is expressed in a few mammalian tissues such as skeletal muscle, heart, and brain. In the heart, sorcin interacts with the ryanodine receptor and L-type Ca2+-channels regulating excitation in contraction coupling. 

In order to accomplish these diverse physiological tasks described above, nature has created at least five different types of Ca2+ channels. These are termed L-, N-, P/Q-, R-, and T-type. Although they are all structurally similar (Fig. 1) they differ with respect to their biophysical properties. Some of them need only weak depolarizations to open and inactivate fast (e.g., T-type Ca2+ channels), whereas others require strong depolarizations and inactivate more slowly (e.g. P- or L-type Ca2+ channels). Channel types also differ with respect to their sensitivity to drugs. This selectivity is exploited for pharmacotherapy. 

At present, only organic blockers of L-type Ca2+ channels (also termed Ca2+ antagonist ) are licensed... 

In the case of L-type Ca2+ channels, they also carry binding sites for Ca2+ antagonist drugs. The accessory a2-5, p, and y subunits stabilize Ca2+ channel function and support its targeting to the plasma membrane. Notably other proteins can associate with the channel complex allowing the formation of signaling complex important for channel targeting and modulation. 

Sinnegger-Brauns MJ, Hetzenauer A, Huber IG et al (2004) Isoform-specific regulation of mood behavior and pancreatic (3-cell and cardiovascular function by L-type Ca2+channels. J Clin Invest 113 1430-1439... 

Welling A, Ludwig A, Zimmer S et al (1997) Alternatively spliced IS 6 segments of the alpha 1C gene determine the tissue-specific dihydropyridine sensitivity of cardiac and vascular smooth muscle L-type Ca2+ channels. Circ Res 81 526-532... 

The first G-protein a subunit to be identified was Gs. The a subunit of Gs (as) is responsible for stimulating adenylate cyclase (hence, the subscript s ) and is ADP-ribosylated and activated by CTx. Gs has at least four molecular variants. Some evidence exists that as can also enhance the activity of cardiac L-type Ca2+ channels, independently of their phosphorylation by cAMP-stimu-lated protein kinase A. Golf is a cyclase-stimulating homolog in the olfactory epithelium, activated by the large family of olfactory receptors. 

L-type Ca2+ channels—L-type calcium channels (in muscles and neurons ... 

The first molecule, the Ca2+ channel, is required for coupling at the triad. Skeletal muscle contains higher concentrations of this L-type Ca2+ channel that can be accounted for on the basis of measured voltage-dependent Ca2+ influx because much of the Ca2+ channel protein in the T-tubular membrane does not actively gate calcium ion movement but, rather, acts as a voltage transducer that links depolarization of the T-tubular membrane to Ca2+ release through a receptor protein in the SR membrane. The ryanodine receptor mediates sarcoplasmic reticulum Ca2+ release. The bar-like structures that connect the terminal elements of the SR with the T-tubular membrane in the triad are formed by a large protein that is the principal pathway for Ca2+ release from the SR. This protein, which binds the... 

Hirst It might also suggest that the site of Ca2+ release is important, even before the mechanisms altering sensitivity come in. As far as I m concerned, Ca2+ going through L-type Ca2+ channels is ineffective at triggering contraction, whereas store-released Ca2+ is much more effective. Even at the level you are talking about, it would be the site of release that is important. 

Fry The voltage dependence of these STOCs that you have shown is interesting, because there is now more evidence for T type Ca2+ currents in smooth muscle cells. Kenton Sanders, you said that it was in the window current for the L-type Ca2+ channels, but it is probably about 10 mV too negative for that. Is there any evidence that T type channel activity will be involved ... 

Curtis TM, Scholfield CN 2001 Nifedipine blocks Ca2+ store refilling through a pathway not involving L-type Ca2+ channels in rabit arteriolar smooth muscle. J Physiol 532 609-623... 

Young We have data showing that induction of a Ca2+ wave in cultured myometrial cells that lack L-type Ca2+ channels causes activation of Ca2+-activated K+ channels that we think are store-operated. This is just with passage of a Ca2+ wave without thapsigargin. 

EGTA and I l uo 4 and simultaneous recordings of Iq, and Ca2+ fluorescence were made. As expected for tight coupling in cardiac myocytes, brief Ca2+ sparks were recorded following activation of Iya (Fig. 3). Conversely, however, coupling between L-type Ca2+ channels and RyRs was completely abrogated in bladder myocytes recorded under identical conditions. 

FIG. 4. Model of RyR-mediated Ca2+ release in muscle. Evidence indicates allosteric coupling between the L-type Ca2+ channel and RyRl in skeletal muscle, tight coupling between the channels in cardiac (RyR2), and loose coupling to localized RyR (probably RyR2) in smooth muscle. 

Nakamura M, Sunagawa M, Kosugi T, Sperelakis N 2000 Actin filament disruption inhibits L-type Ca2+ channel current in cultured vascular smooth muscle cells. Am J Physiol 279 0480-0487... 

Phase 2 A plateau occurs owing to the opening of L-type Ca2+ channels, which offset the action of K+ channels and maintain depolarization. During this phase, no further depolarization is possible. This is an important point to demonstrate and explains why tetany is not possible in cardiac muscle. This time period is the absolute refractory period (ARP). The plateau should not be drawn completely horizontal as repolarization is slowed by Ca2+ channels but not halted altogether. 

Phase 3 The L-type Ca2+ channels close and K+ efflux now causes repolarization as seen before. The relative refractory period (RRP) occurs during phases 3 and 4. 

Zapata-Sudo G etal Is comparative cardiotoxicity of S(-) andR(+) bupivacaine related to enantiomer-selective inhibition of L-type Ca2+ channels Anesth Analg 2001 92 496. [PMID 11159257]... 

We have focused on the identification of natural key compounds that possess biologically and medicinally intriguing functions. Some of bioactive naturally occurring compounds isolated from marine organisms were found to possess unique biological activities. Halichlorine from the marine sponge Halichondria okadai was shown to inhibit the activity of nuclear factor- in endothelial cells and block L-type Ca2+ channels. Thus, it may have therapeutic potentials for diseases such as atherosclerosis and hypertension. 

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