Molecular determinants of voltage-dependent gating in T-type calcium channels

点击翻译按钮获取中文摘要

The nerve cell, or neuron, is the key player in the activity of the nervous system. It conveys information both electrically and chemically. The mechanism underlying signal transmission within neurons is based on voltage differences that exist between the inside and the outside of the cell. This membrane potential is created by the uneven distribution of electrically charged particles, or ions, such as sodium (Na), potassium (K), chloride (Cl), and calcium (Ca). These ions enter and exit the cell through specific protein channels (ion channels) in the cell's membrane. The channels "open" or "close" in response to changes in the cell's membrane potential. The resulting redistribution of electric charges may alter the voltage difference across the membrane. A decrease in the voltage difference is called depolarization. If depolarization exceeds a certain threshold, an impulse (i.e., action potential) will travel along the neuron. The depolarization causes Ca to enter the cell through calcium channels. Hence calcium channels play an important role in neurotransmission. Over the last 20 years, three (3) different families of calcium channel proteins have been identified and characterized based upon their pharmacological, genetic and voltage sensitivities. The T-type (CaV3) channels are atypical channels that open and close much more rapidly than CaV1 and CaV2 channels. We know relatively little about the molecular mechanisms underlying these differences. We propose to identify the molecular and cellular elements controlling the rate at which T-type calcium channels open and close in response to membrane potential. An array of molecular, biochemical, and cellular techniques will be used to answer these questions. The function of mutant channels will be studied using electrophysiological and protein chemistry techniques. The behavior of the mutants will then be analyzed by computer modeling to simulate by computer the channel structure. This knowledge will provide valuable insight into future pharmacological therapies such as improved calcium channel blockers.