Ion channels are crucial for diverse physiological functions, ranging from muscle contraction to hormone secretion, rhythmic beating of the heart to signaling in the brain. They selectively conduct ions across the cell membrane in response to changes in membrane potential or binding of a ligand. This research proposal seeks to understand the molecular and biophysical basis of ion permeation and gating of two types of ion channels, the inwardly rectifying K+ (Kir) channels and voltage-gated Ca2+ channels, both of which are abundant in heart and brain. Kir channels conduct less K+ during membrane depolarization due to block by cytoplasmic Mg2+ ions and polyamines and are regulated by a membrane phospholipid, PIP2. They play an important role in maintaining the resting membrane potential and regulating neuronal excitability, heart beat and hormone secretion. Voltage-gated Ca2+ channels mediate Ca2+ entry into cells in response to membrane depolarization and are vital for heartbeat and neurotransmitter release. We will use a combination of molecular biological, chemical and electrophysiological methods to investigate the structural features of the ion permeation pathway and mechanisms of channel gating. The proposed projects are: (1) to study the mechanism by which intracellular Mg2+ ions induce subconductance levels in Kir channel; (2) to examine the activation gate and conformational changes associated with PIP2 regulation of Kir channels; (3) to identify structural elements and amino acids that form the inner pore of Ca2+ channels; (4) to explore the molecular architecture of the selectivity filter including its size and the spatial organization of the four glutamates that are critical for Ca2+ selectivity and permeation; (5) to examine the activation gate and conformational changes associated with voltage-dependent activation of Ca2+ channels.Mutations in both Kir and Ca2+ channels have been found to cause neurological disorders in humans. Studies on the molecular mechanisms of ion permeation and gating of these channels are therefore important for understanding their physiological functions under normal conditions and in disorders such as arrhythmia, epilepsy and migraine. They may also help in the development of pharmacological agents directed at these channels.
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