Modulation and pharmacology of low voltage-activated (T-type) calcium channels

Although T-type calcium channel currents were observed almost 30 years ago, the genes that encode the pore-forming subunits have only been recently reported. When expressed in heterologous systems, three distinct alpha1 subunits (alpha1G (Ca(v)3.1), alpha1H (Ca(v)3.2), and alpha1I (Ca(v)3.3)) conduct T-type currents with insert similar but not identical electrophysiological characteristics that. Alpha1G, alpha1H, and alpha1I transcripts are found throughout neural and nonneural tissues, suggesting multiple types of T-type channels (also called low voltage-activated calcium channels (LVAs)) are coexpressed by many tissues. The study of endogenous LVAs has been hampered by a lack of highly selective antagonists that differentiate between LVA subtypes. Furthermore, many pharmacological agents attenuate currents conducted by LVA and high voltage-activated calcium channels (HVAs). At least 15 classes of pharmacological agents affect T-type currents, and the therapeutic use of many of these drugs has implicated LVAs in the etiology of a variety of diseases. Comparison of the responses of recombinant and native LVAs to pharmacological agents and endogenous modulatory molecules will lead to a better understanding of LVAs in normal and diseased cells.