Structure, function and regulation of CaV2.2 N-type calcium channels

Abstract

N-type or Ca V 2.2 high-voltage activated calcium channels are distinguished by exclusively neuronal tissue distribution, sensitivity to ω-conotoxins, prominent inhibition by G-proteins, and a unique role in nociception. Most investigated modulatory pathway regulating the Ca V 2.2 channels is G-protein-coupled receptor-activated pathway leading to current inhibition by Gβγ subunit of G-protein. Binding of Gβγ dimer to α 1 subunit of the Ca V 2.2 channel transfers the channel form "willing" to "reluctant" gating state. Channel phosphorylation by protein kinase C potentiates N-type calcium current. Ca V 2.2 channels could be functionally regulated also by a number of protein-protein interactions. Ca V 2.2 null mice are hyposensitive to inflammatory and neuropathic pain, otherwise they have a mild phenotype. Consistent with the mild phenotype of the Ca V 2.2 -/mice, reports on mutations linked to a disease phenotype are scarce. Only one mutation related to human heritable diseases was identified until now. Pharmaceutical inhibition of Ca V 2.2 channels either by direct inhibition of the channel, by an activation of G-protein coupled receptors, or by inhibition of membrane targeting of the channel protein are promising strategies for treatment of severe chronic and/or neuropathic pain.

Modulation of voltage-gated CaV2.2 Ca2+ channels by newly identified interaction partners

“…Schematic depiction of the role of presynaptic Ca V 2.2 in signal transmission in a nociceptive synapse. Modified from [22] with permission. agonist binding to GPCRs, the heterotrimeric G-protein splits into a G α monomer and a Gβγ dimer.…”

“…Modulation of the N-type Ca 2+ channels by G-proteins is most extensively studied and was recently reviewed by several authors [20][21][22][23]. To describe the alteration of channel gating upon interaction with G-proteins, a model of "willing" and "reluctant" gating states was introduced [24,25].…”

“… Schematic depiction of the role of presynaptic Ca V 2.2 in signal transmission in a nociceptive synapse. Modified from [ 22 ] with permission. …”

Structural and Functional Analyses of Cone Snail Toxins

“…Ca v 2.2 channel subtypes are known as N-type because they are exclusively neuronal and express a Ca ++ current component that is different from L-type (Ca v 1.1–Ca v 1.4) or T-type (Ca v 3.1−Ca v 3.3) components [176,179]. Thus, these channel subtypes are involved in nociception more than in any other physiologic process [180]. Interestingly, from of MVIIA, a ω-conotoxin purified from Conus magus venom, was developed Prialt TM as drug for the treatment of neuropathic pain [181].…”

A novel ω-conotoxin Bu8 inhibiting N-type voltage-gated calcium channels displays potent analgesic activity

“…To date, 22 ω -conotoxins which inhibit L-(Ca V 1.1), N-(Ca V 2.2) and P/Q-type (Ca V 2.1) calcium channels have been characterized with several of these conotoxins specifically targeting Ca V 2.2 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 . Ca V 2.2 is highly expressed in superficial layers of the spinal cord and dorsal root ganglion neurons and modulates pain and other physiological signal processing 22 , 23 , 24 . Currently, one ω -conotoxin MVIIA (ziconotide) has been approved as an analgesic by the U.S. Food and Drug Administration (FDA) 25 .…”