Molecular and Cellular Basis of Ion Channels in Physiology and Pathophysiology

Ion channels are crucial components for the activity of living cells. They are integral proteins in the cell membrane and allow particular ions to pass through them. The transmembrane movement of ions through specific channels is a fundamental mechanism in the regulation of cell function in all tissues. Modifications of the activities of these ion channels well evoke changes in the membrane potential that are associated with the inhibition, modulation or termination of cellular activities. The changes of ion channel activities play very important roles in many physiological and pathophysiological processes. My long-term research goal is to understand the molecular and cellular basis of ion channels, regulation of ion channels, and their roles in inherited and environmentally-induced diseases and to provide useful information towards developing new preventive and therapeutic methods in the management and/or rectification of pathophysiological conditions.

My major research works focus on voltage-gated calcium (Ca²⁺) channels. Voltage-gated Ca²⁺ channels found in all excitable cells and many non-excitable cells mediate Ca²⁺ ion influx in response to membrane depolarization. Ca²⁺ entering into cell through voltage-gated Ca²⁺ channels regulates several biological processes including gene transcription, muscle contraction, hormone secretion, and neurotransmitter release. Ca²⁺ channels are classified into several groups (L-, N-, P/Q-, R- and T-types) based on their electrophysiological, molecular biological and pharmacological properties. They are composed of four principal subunits: the transmembrane, pore-forming a_l subunits and three accessory subunits that modulate channel function--the glycosylated a₂d subunits, the integral membrane g subunits, and the cytoplasmic ß subunits. There are several isoforms of each of these channel subunits, and the composition of the channel complex determines its expression level, localization, kinetics, and pharmacology. The activity of Ca²⁺ channels is regulated by a wide variety of intracellular signaling pathways. Probably the three most well understood are binding and activation of calmodulin, phosphorylation by several protein kinases, and binding of G protein bgsubunits. These pathways not only modulate Ca²⁺ channel activity, all are themselves modulated in various ways by Ca²⁺ influx through Ca²⁺ channels, and many interact with one another. Thus, complex feedback mechanisms among Ca²⁺ channels and intracellular signaling exist and are likely targets for both environmental toxicants and genetic disorders. There are two fundamentally different mechanisms that might alter Ca²⁺ channel function: by direct interaction with channel subunits (e.g., block the pore) or by interaction with intracellular signaling pathways that modulate channel activity. A large number of neurotransmitters or toxicants are known to alter intracellular signaling pathways and/or alter Ca²⁺ homeostasis, but how these effects impact Ca²⁺ channel function remains largely unexplored. Therefore, to understand cellular and molecular mechanisms of modulation of Ca²⁺ channel activities will be increase our understanding of their roles in physiology and pathophysiology, as well as potential target for therapeutics.