Signal Integration by Ion Channels

Ion channels are dynamic proteins that confer excitability to neurons and cardiac, immune, and secretory cells. Ion channels are modulated by a diverse array of stimuli: voltage, extracellular agonists, lipids, temperature, ionic concentration, G proteins, and physical stretch. I am interested in understanding how ion channels integrate input on molecular and cellular levels.

Molecular Signal Integration: What are the conformational steps that allow ion channels to integrate diverse environmental inputs to the status of the pore? I am investigating allosteric regulation in transient receptor potential M (TRPM) channels. Current structural data provides only limited snapshots of protein conformations. We use FRET and FLIM alongside electrophysiology to uncover the dynamic movements TRPM2 channel modules undergo in response to ADP ribose, Ca2+, heat, and the phosphoinositide PtdInsP2.

Cellular Signal Integration: How do G protein coupled receptors, phosphoinositides, and membrane trafficking combine to impact ion channel function? An upcoming project will investigate the regulation and trafficking of TRPM3 channels. We will use FRET, electrophysiology, and click labeling to look at the cellular signaling dynamics of wildtype and mutated TRPM3. TRPM3 mutations are implicated in developmental and epileptic encephalopathies, cataracts, and myalgic encephalomyelitis/chronic fatigue syndrome.