L-type calcium channel activity

Table 7 Modulation of hERG and L-type calcium channel activity following fluorine substitution...

Expansion of other adult cell populations have also been investigated for potential clinical application, including the expansion of pancreatic p-cells with small molecules such as the Wnt agonist la, indicating a further role for Wnt signalling in pancreatic cell proliferation, and the L-type calcium channel activator 2a, which was observed to exert an additive effect when used in conjunction with a GLP-1 receptor agonist, Exendin-4. ... 

Thibault, O., Hadley, R. Landfield, RW. (2001). Elevated postsynaptic [Ca " ] and L-type calcium channel activity in aged hippocampal neurons relationship to impaired synaptic plasticity. Journal of Neuroscience, 21, 9744-9756. 

Protein kinase A (PKA) is a cyclic AMP-dependent protein kinase, a member of a family of protein kinases that are activated by binding of cAMP to their two regulatory subunits, which results in the release of two active catalytic subunits. Targets of PKA include L-type calcium channels (the relevant subunit and site of phosphorylation is still uncertain), phospholam-ban (the regulator of the sarcoplasmic calcium ATPase, SERCA) and key enzymes of glucose and lipid metabolism. 

A large number of diugs interfere with the smooth muscle contraction. These compounds lower blood pressure and are referred to as antihypertensive. In this section, only those coumpounds will be mentioned that have a direct effect on smooth muscle tone. Phenylephrine is an agonist on most smooth muscles and activates ax adrenoceptors. Carbachol is an agonist on some smooth muscles and activates contraction through muscarinic receptors. Blockers of the ax-adrenoceptors such as prazosin and urapidil are competitive inhibitors of the ax-receptor in vascular and bladder smooth muscle. Phenoxybenzamine is an ineversible blocker of ax receptors and phentol-amine blocks ax and a2 receptors. Ca2+ channel blockers such as the dihydropyiidines, phenylalkyla-mines and benzothiazepines lower smooth muscle tone by blocking the L-type calcium channel. 

L-type calcium channels (voltage-gated calcium channels L-subtype) Similarity to Diltiazem and a second ligand. ZINC db ( 50 K commercially available subset screened but most filtered to achieve desired PK profile using VolSurf). SHOP similarity, and feature-presence filtering down to 36 compounds 7 hits 18 tested, active in a vasorelaxant assay and some had novel structures. [67]... 

FIGURE 2 Examples of the variety of structures obtained in natural product screens. I, zaragozic acid A, is an inhibitor of mammalian and fungal sterol synthesis, obtained from fungi (48) II, L-696,474, is an inhibitor of the HIV protease, obtained from fungi (51) III, dehydrosoyasaponin I, is an agonist of the calcium-activated potassium channel, obtained from a medicinal plant (58) IV, tetrandrine, is an inhibitor of L-type calcium channels, obtained from a plant (78). 

Verapamil blocks both activated and inactivated L-type calcium channels. Thus, its effect is more marked in tissues that fire frequently, those that are less completely polarized at rest, and those in which activation depends exclusively on the calcium current, such as the sinoatrial and atrioventricular nodes. Atrioventricular nodal conduction time and effective refractory period are invariably prolonged by therapeutic concentrations. Verapamil usually slows the sinoatrial node by its direct action, but its hypotensive action may occasionally result in a small reflex increase of sinoatrial nodal rate. 

Jorgensen NR, Teilmann SC, Henriksen Z, Civitelli R, Sorensen OH, Steinberg TH. 2003. Activation of L-type calcium channels is required for gap junction-mediated intercellular calcium signaling in osteoblastic cells. J Biol Chem 278 4082—6. 

Genistein (42) was found to affect many other types of channels, but the main proposed mechanism of these interactions was indirect. In most cases a PTK pathway was suggested as a putative explanation of the observed effects. Since genistein (42) is a well-known inhibitor of this kinase, we will not focus on those papers and only a short list will be presented. Such a mechanism was mentioned in the case of inhibition of ATP-sensitive K+ channels [325], cardiac slowly activating delayed-rectifier K+ current [326], L-type calcium channels [327,328] (contrary to the direct interaction proposed by Chiang et al. [306] and Yokoshiki et al. [307]), P/Q-type calcium channels in rat hippocampal neurons [329], and carotid baroreceptor activity [330]. A PTK-dependent mechanism was also proposed as the explanation of potentiation of neuronal a7 nAGhRs by genistein (42) [331]. 

The (—) isomer of the L-type calcium channel blocker (+)-niguldipine is dexniguldipine. This agent binds to an intracellular domain of P-gp with a K, of 10 nm. In addition, this compound can block RNA synthesis at 5 pM and possesses some anticancer activity (302). Currently, only a few studies have been conducted to evaluate the use of this compound as a P-gp modulator. Definitive results are yet to be reported. 

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. 

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