Host: The Japanese Pharmacological Society, The Japanese Society of Clinical Pharmacology
Name : WCP2018 (18th World Congress of Basic and Clinical Pharmacology)
Location : Kyoto
Date : July 01, 2018 - July 06, 2018
Voltage-gated calcium channels of the CaV2 sub-family are involved in neurotransmitter release in the central and peripheral nervous systems. CaV2.2 channels (N-type) are of particular importance in neurotransmission in primary afferent terminals mediating pain transmission. These channels are heteromeric. The alpha1 pore-forming subunit is associated with auxiliary beta and alpha2delta subunits which increase the functional expression and modify channel properties. alpha2delta-1 plays a key role in rodent models of neuropathic pain and in development of neuropathic mechanical hypersensitivity and allodynia. The mRNA and protein for alpha2delta-1 is strongly up-regulated in injured dorsal root ganglion neurons and such injuries lead to a chronic neuropathic pain-state (1,2).
We have studied the role of the auxiliary alpha2delta subunits in CaV2.2 (N-type) calcium channel trafficking and function (3) and the key functions of their Von-Willebrand factor domain in this process (3-5). Furthermore our recent work shows that proteolytic cleavage of alpha2delta subunits into alpha2 and delta is essential for most of their effects (6). I will describe studies which increase our understanding of the roles of alpha2delta subunits using knock-in mice containing tagged calcium channels.
References
1 Bauer C. S. et al. The increased trafficking of the calcium channel subunit a2d-1 to presynaptic terminals in neuropathic pain is inhibited by the alpha2delta ligand pregabalin. Journal of Neuroscience 29 4076-4088 (2009).
2 Patel R. et al. alpha2delta-1 gene deletion affects somatosensory neuron function and delays mechanical hypersensitivity in response to peripheral nerve damage. J Neurosci 33 16412-16426 (2013).
3 Cassidy J. S et al. Functional exofacially tagged N-type calcium channels elucidate the interaction with auxiliary alpha2delta-1 subunits. Proc. Natl. Acad. Sci. U. S. A 111 8979-8984 (2014).
4 Canti C. et al. The metal-ion-dependent adhesion site in the Von Willebrand factor-A domain of alpha2delta subunits is key to trafficking voltage-gated Ca2+ channels. Proc. Natl. Acad. Sci. USA 102 11230-11235 (2005).
5 Hoppa M. B., et al. alpha2delta expression sets presynaptic calcium channel abundance and release probability. Nature 486 122-125 (2012).
6 Kadurin I. et al. Proteolytic maturation of alpha2delta represents a checkpoint for activation and neuronal trafficking of latent calcium channels ELife 5 e21143 (2016).
