Gerry S. Oxford Professor, (past)

Regulation of Ion Channels and Receptors involved in Neurosecretion and in Pain Sensation.

Research in my laboratory is divided into two main themes both of which are focused on the mechanisms by which ion channels control the passage of Na+, K+, and Ca2+ ions across neuronal cell membranes. The first theme deals with the signaling events coupling G-protein coupled receptors and ion channels and how these signals regulate the process of neurotransmitter and hormone secretion. The second theme involves structural and functional analyses of the capsaicin receptor (TRPV1), the key membrane protein which transduces noxious chemical and thermal stimuli into the sensation of pain. We employ patch clamp electrophysiology to study membrane potentials, ion currents, and single channel events combined with biochemistry, molecular mutagenesis, and novel digital image analysis procedures to measure intracellular ions and secretory activity from individual neurons.

The following projects are among those underway in our laboratory:

• We are interested in the mechanisms underlying differential desensitization of receptors. The dopamine receptors (D2 and D3) activate GIRK channels similarly, but exhibit very different desensitization properties. The TRPV1 receptor desensitizes to capsaicin, but only in the presence of extracellular calcium. We are exploring the structural features of these receptors which regulate their broad spectrum of desensitization behavior.
• Peripheral nociceptors become hypersensitized to sensory inputs following injury and inflammation. This sensitization is accompanied by elevation of many chemicals, including nerve growth factor (NGF). We have demonstrated that NGF sensitizes TRPV1 receptor responses in DRG neurons and in CHO cells engineered to co-express NGF (trkA) and TRPV1 receptors. We are examining the molecular mechanisms underlying this sensitization.
• It is widely assumed that signaling pathways activated by binding of one selective agonist to a particular GPCR will also be activated by any other agonist of that receptor. We have recently observed that activation of D2 receptors by prototypical agonists (e.g. quinpirole) will trigger signaling to cAMP, GIRK channels, calcium channels, and MAP kinase. However, activation of the same receptors by novel agonists activate only a subset of pathways. We are exploring the molecular mechanisms underlying this "functional selectivity" for signaling by a single receptor and assessing the involvement of G-protein subunits, receptor oligomerization, RGS proteins, and protein scaffolding.