Research in our lab is supported by the grants from the CHDI Foundation, the Welch Foundation, the NINDS at National Institutes of Health and the NIA at National Institutes of Health.

Our main interest is in calcium signaling. Calcium ion (Ca2+) acts as an intracellular second messenger in living cells. Changes in the cytosolic Ca2+ level influence most fundamental cellular processes. Deranged calcium signaling results in a number of disorders. Local and rapid changes in cytosolic Ca2+ are evoked by activation of plasma membrane voltage-gated Ca2+ channels in response to membrane depolarization. Global changes in cytosolic Ca2+ are supported by intracellular Ca2+ release channels - the inositol (1,4,5)-trisphosphate receptor (InsP3R) and ryanodine receptor (RyanR). The functional properties and modulation of intracellular Ca2+ release channels and voltage-gated Ca2+ channels is the focus of our research.

The main directions of our research are:

Structure-function and modulation of the inositol trisphosphate receptor (InsP3R)

We use molecular, biochemical, imaging, and electrophysiological methods to study properties of InsP3R [1, 2, 6, 10, 11, 15, 19, 22, 23, 24, 13, 14, 18, 13, 21]. Our emphasis is on understanding how the activity of these channels is modulated.

Deranged calcium signaling and neurodegenerative disorders

In the course of our studies of InsP3R we discovered a connection between deranged neuronal calcium signaling and Huntington's disease (HD) [16, 20, 27, 33, 35, 38, 39, 41, 43, 44, 49, 53, 56]. Currently we are expanding this area of research to other neurodegenerative diseases, such as spinocerebellar ataxia type 3 (SCA3) [42], spinocerebellar ataxia type 2 (SCA2) [46, 58, 59] and Alzheimer's Disease (AD) [31, 34, 50, 51, 54]. We are also developing new therapeutic agents for HD and AD [55, 60] and study structures of proteins involved in neurodegenerative disorders [47, 61]. We hope that our research will help in developing therapeutics for these incurable and lethal disorders.

Synaptic voltage-gated calcium channels

In the nervous system, secretion of neurotransmitter is triggered by Ca2+ influx via presynaptic voltage-gated Ca2+ channels. We are trying to understand the molecular mechanisms involved in targeting voltage-gated Ca2+ channels to synpatic locations [3, 12, 25, 26, 30]. This work also prompted us to examine general rules that govern PDZ domain ligand specificty using a bioinformatics approach [9] and to develop a high-throughput screen for small molecule PDZ domain inhibitors [37].