How “Pharmacoresistant” is Cav2.3, the Major Component of Voltage-Gated R-type Ca2+ Channels?

Abstract

Membrane-bound voltage-gated Ca2+ channels (VGCCs) are targets for specific signaling complexes, which regulate important processes like gene expression, neurotransmitter release and neuronal excitability. It is becoming increasingly evident that the so called “resistant” (R-type) VGCC Cav2.3 is critical in several physiologic and pathophysiologic processes in the central nervous system, vascular system and in endocrine systems. However its eponymous attribute of pharmacologic inertness initially made in depth investigation of the channel difficult. Although the identification of SNX-482 as a fairly specific inhibitor of Cav2.3 in the nanomolar range has enabled insights into the channels properties, availability of other pharmacologic modulators of Cav2.3 with different chemical, physical and biological properties are of great importance for future investigations. Therefore the literature was screened systematically for molecules that modulate Cav2.3 VGCCs.

Voltage-Gated R-Type Calcium Channel Inhibition via Human μ-, δ-, and κ-opioid Receptors Is Voltage-Independently Mediated by Gβγ Protein Subunits

“…Although they are recognized as potential drug targets for treating chronic pain, their mode of regulation is poorly understood (Schneider et al, 2013;Rittenhouse, 2014). Here, we demonstrate that Ca v 2.3 channels are efficiently modulated via m-, d-, or k-OR activation.…”

“…Ca v 2.3 channels are localized to somatodendritic and presynaptic regions of various central and peripheral neurons and are also expressed in endocrine cells (Schneider et al, 2013). Although they are recognized as potential drug targets for treating chronic pain, their mode of regulation is poorly understood (Schneider et al, 2013;Rittenhouse, 2014).…”

Cav2.3 channels contribute to dopaminergic neuron loss in a model of Parkinson’s disease

“…Inhibition of Cav2.3—alone or in combination with inhibition of L-type and/or T-type voltage-gated Ca 2+ channels 14,23 —could form the basis of a neuroprotective strategy for Parkinson’s disease in the future. However, the only available Cav2.3 inhibitor (SNX-482) is unsuitable for neuroprotection in a clinical setting due to off target effects 28,43,75 . Thus, development of high affinity, brain-permeable, and selective Cav2.3 channel blockers is warranted 28,75 .…”

“…However, the only available Cav2.3 inhibitor (SNX-482) is unsuitable for neuroprotection in a clinical setting due to off target effects 28,43,75 . Thus, development of high affinity, brain-permeable, and selective Cav2.3 channel blockers is warranted 28,75 .…”

α-Conotoxin Vc1.1 inhibits human dorsal root ganglion neuroexcitability and mouse colonic nociception via GABABreceptors

“… 35 40 Cav2.2 channels mediate the neuronal N-type calcium current, 49 whereas Ca V 2.3 channels typically conduct a small proportion of the whole-cell calcium current, known as the R-type calcium current. 53 Inhibition of Ca V 2.2, by either gene knockout or selective channel antagonists, causes analgesia in neuropathic pain models. 49 Notably, Ca V channels have been demonstrated in several studies to contribute to the rheobase of neurons.…”