T-type Calcium Channels: Functional Regulation and Implication in Pain Signaling

Low-voltage-activated T-type Ca2+ channels (T-channels), especially Ca(v)3.2 among the three isoforms (Ca(v)3.1, Ca(v)3.2, and Ca(v)3.3), are now considered to play pivotal roles in processing of pain signals. Ca(v)3.2 T-channels are functionally modulated by extracellular substances such as hydrogen sulfide and ascorbic acid, by intracellular signaling molecules including protein kinases, and by glycosylation. Ca(v)3.2 T-channels are abundantly expressed in both peripheral and central endings of the primary afferent neurons, regulating neuronal excitability and release of excitatory neurotransmitters such as substance P and glutamate, respectively. Functional upregulation of Ca(v)3.2 T-channels is involved in the pathophysiology of inflammatory, neuropathic, and visceral pain. Thus, Ca(v)3.2 T-channels are considered to serve as novel targets for development of drugs for treatment of intractable pain resistant to currently available analgesics.