University of Virginia Health System

Calcium entry via voltage-gated Ca2+ channels is a key event in neuronal firing, muscle contraction, gene expression, and secretion of neurotransmitters and hormones. Voltage-gated Ca2+ channels are the site of action of a number of clinically relevant drugs, termed "calcium channel blockers." Typically these drugs are used to treat hypertension and angina, but recent evidence suggests that similar blockers might be useful for epilepsy and pain.

The Perez-Reyes laboratory is focused on determining the molecular structure of voltage-gated calcium channels, then studying how their structure relates to the function and pharmacology of the channel (review). Early studies focused on the cloning and expression of the skeletal and cardiac muscle L-type channels. These studies established that the alpha1 subunit contains both the ion permeation pathway and is the receptor for most calcium channel blockers. These studies also elucidated the important role that auxiliary subunits play in the formation of active channels and drug receptors. A key contribution was the cloning of low voltage-activated T-type Ca2+ channels, which has opened the door to studies on their biophysics, localization, role in neuronal excitability, and pharmacology. This work combined a number of exciting techniques such as bioinformatics, molecular cloning, and electrophysiological recordings of whole cell and single channel currents. We believe that up regulation of T-type channels may underlie many pathological states including thalamocortical dysrhythmias and epilepsy. To test this hypothesis we have examined their expression in animal models of epilepsy and studied how anti-epileptic drugs block the recombinant channels. Future work will be directed at regulating T-type channel levels in the brain, and studying the functional consequences of knocking out gene expression in transgenic mice. The laboratory is currently funded by grants from NIH.