Getting a handle on Ca V 2.2 (N-type) voltage-gated Ca 2+ channels

Abstract

In PNAS, Nieto-Rostro et al. (1) report a mouse model expressing CaV2.2 (N-type) voltage-gated Ca2+ channels (VGCCs) with an extracellularly accessible hemagglutinin (HA) epitope tag engineered into their pore-forming CaV2.2 α1 subunits (i.e., CaV2.2_HAKI/KI mice). This model allowed the identification of endogenous CaV2.2 channels in the plasma membrane of peripheral somatosensory neurons and the role of accessory α2δ-1 subunits for their plasma membrane targeting. These mice expand our biochemical tools to reveal disease-associated changes in the subcellular distribution of CaV2.2 channels in the pain pathway and other neurons with high sensitivity and specificity, which can eventually help to answer the still-unresolved question of whether CaV2.2 Ca2+ channels are suitable targets for novel analgesic therapies. Chronic pain (defined as >3 mo of pain) is a major medical issue impairing the physical and social well-being of patients and their overall quality of life. It is estimated to affect ∼1.5 billion people globally and 50 million adults in the United States (2, 3). Neuropathic pain especially causes a high disease burden, and therapeutic options are limited. Neuropathic pain is caused by damage of the somatosensory nerves due to direct lesions (e.g., peripheral nerve injury), infections (e.g., postherpetic neuralgia), diabetic neuropathy, or neurotoxic substances (e.g., antitumor drugs) (4). Current treatments, like antiepileptics [e.g., the gabapentinoids (GBPs) gabapentin and pregabalin], antidepressants (amitrytiline and duloxetine), and topical capsaicin, are often unsatisfactory. There is a high unmet medical need for new analgesics, which requires not only a better understanding of how currently used analgesics work but also the discovery of novel drug targets. Progress in clinical development of new drugs to treat severe chronic pain has been slow despite exciting reports of efficacy in animal models. Ion channels, which … [↵][1]1Email: joerg.striessnig{at}uibk.ac.at. [1]: #xref-corresp-1-1