Molecular Pharmacology of Non-L-type Calcium Channels

Abstract

Voltage-gated calcium channels are key sources of calcium entry into the cytosol. Mutations in calcium channels have been implicated in numerous disorders such as migraine, incomplete congenital X-linked stationary night blindness, epilepsy, and ataxia, and they are important therapeutic targets for the treatment of pain, stroke, hypertension, and epilepsy. Calcium channel antagonists can be broadly classified into three groups. 1) Inorganic ions typically nonselectively block the pore of most calcium channel subtypes, and in some cases, alter gating kinetics. 2) Peptides isolated from arachnids, cone snails, and snakes frequently selectively antagonize individual calcium channel subtypes by direct occlusion of the pore or altering gating kinetics. 3) Small organic molecules of various structure-activity-relationship (SAR) classes can mediate both selective and nonselective effects on individual calcium channel subtypes, and occlude the pore or reduce channel availability. Here, we provide an overview of classes of inhibitors of non-L-type calcium channels.

Pathways-based analyses of whole-genome association study data in bipolar disorder reveal genes mediating ion channel activity and synaptic neurotransmission

“…Fourth, multiple genetic disorders with both strong characteristic similarities and high comorbidity with bipolar disorder (e.g., epilepsy, migraines) are known to be caused by any one of a number of ion channel or ion-transporting ATPase mutations (BahiBuisson et al 2007;Castro et al 2007;Chandy et al 2006;Dichgans et al 2005;Doering and Zamponi 2005;Fernandez et al 2008;Graves 2006;Grisar et al 1992;Kors et al 2002;Mossner et al 2005;Nappi et al 2000).…”

Presynaptic Calcium Channels: Structure, Regulators, and Blockers

“…As mentioned earlier, the pharmacological profile of a given calcium channel is a key means of identifying a particular calcium channel subtype. While small organic molecules such as dihydropyridines have been used to definitively characterize L-type calcium channels (Bean 1984), peptide toxins isolated from fish-hunting marine snails, spiders, scorpions, and snakes have been an invaluable source of selective inhibitors of synaptic calcium channels (Doering and Zamponi 2005). The archetypal N-type calcium channel inhibitor is ω-conotoxin GVIA, a peptide isolated from the fish-hunting cone snail Conus geographus.…”

“…Besides peptide toxins, presynaptic calcium channels can also be inhibited by divalent metal ions such as cadmium, and by a number of different classes of small organic molecules (Doering and Zamponi 2005). While there are, to our knowledge, no selective small organic inhibitors of P/Q-type calcium channels, substantial efforts are being made to develop small organic N-type channel blockers for use as analgesics which can be administered orally.…”

Editorial [Hot Topic: Membrane Channels as Therapeutic Targets (Executive Editor: Jean-Claude Herve)]

“…Voltage-gated channels are key sources of Ca 2+ entry into the cytosol ; Doering and Zamponi [2] provide an overview of classes of inhibitors of non-L-type calcium channels. However, prolonged elevation of [Ca 2+ ] i above about 10 µM is deleterious to a cell and can activate apoptosis.…”