Gated Calcium Channels

Calcium channel antagonists relax smooth muscle by inhibiting calcium entry and, therefore, have similar functional effects and therapeutic applications to the ATP-gated potassium channel agonists just discussed. Calcium channel antagonists have been widely used therapeutically to treat cardiovascular disorders and were available prior to the discovery of compounds such as cromakalim. 

There are three major classes of calcium channel antagonists. Dihydropyridines (e.g., nifedipine) have significant effects on vascular smooth muscle and 

Nimodipine is a member of the dihydropyridine class of antagonists that improves the outcome of patients following subarachnoid hemorrhage (Wadsworth and McTavish, 1992). This agent relaxes cerebrovascular smooth muscle and reduces the incidence of cerebral vasospasm. Nicardipine has also been demonstrated to have similar efficacy (Haley et al., 

In the kidney, dihydropyridines have been reported to reduce vasoconstriction on the afferent arterioles without affecting efferent resistance (Loutzenhiser and Epstein, 1985). This profile appears to be unique to the dihydropyridine class since members of the other classes did not have preferential effects on the afferent side. The resulting increase in renal perfusion and glomerular filtration rates leads to improved kidney function. In humans with induced renal insufficiency, nifedipine was shown to improve renal performance (Neumayer et al., 1989 Russo et al., 1990). 

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Catterall WA, Perez-Reyes E, Snutch TP et al (2005) International Union of Pharmacology. XLVIII. Nomenclature and structure-function relationships of voltage-gated calcium channels. Pharmacol Rev 57 411-425... 

Furthermore, PKCe is required for nerve growth factor-induced activation of mitogen-activated protein kinases and neurite outgrowth by ethanol. It is also required for ethanol-induced increases in N-type voltage-gated calcium channels in PC 12 neural cells. 

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]... 

In this chapter, we provide a brief overview of voltage-gated calcium channel subtypes and function, with an emphasis on neuronal transmission. The structure and kinetics of calcium channels is an extensive field of study, and outstanding reviews have recently appeared [3,4]. This chapter is focused on the potential opportunities for small-molecule intervention in neuronal signaling via antagonism of voltage-gated calcium channel subtypes, with a brief review of the chemotypes that have been recently reported to modify channel function. 

Table 1 Nomenclature of voltage-gated calcium channels... 

A (590). Ruthenium Red (Section III.D.3) affects the performance of calcium channels (529,591) by interaction with carboxylates at protein-binding sites. The Ruthenium Red is said to block the channel by forming a 1 1 complex at a site in the extracellular entrance to the channel pore, at least for certain neuronal voltage-gated calcium channels (592). 

Catterall, W. A. Structure and regulation of voltage-gated calcium channels. Annu. Rev. Cell Dev. Biol. 16, 521-555, 2000. 

Dolphin, A. C. G protein modulation of voltage-gated calcium channels. Pharmacol. Rev. 55 607-627, 2003. 

Pinto, A., Iwasa, K., Newland, C., Newsom-Davis, J. and Lang, B. The action of Lambert-Eaton myasthenic syndrome immunoglobulin G on cloned human voltage-gated calcium channels. Muscle Nerve 25 715-724, 2002. 

Ertel EA, Campbell KP, Harpold MM et al 2000 Nomenclature of voltage-gated calcium channels. Neuron 25 533-535... 

Keywords CS-syndrome Neurotransmitter release Pyrethroids T-syndrome Voltage-gated calcium channels Voltage-gated sodium channels... 

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