2006-Present Clinical Associate Professor, IPN, Washington State University, Pullman, WA
Ion channels are integral proteins that facilitate the movement of ions between the intracellular and extracellular spaces. The selective movement of ions produces an uneven distribution of charge across the plasma membrane, resulting in a membrane potential (or a change in the membrane potential). Because the electrical properties of virtually all living cells are critically determined by the expression and activity of ion channels, the regulation of ion channel function is profoundly important to cellular and systems physiology. Several regulatory mechanisms of ion channel activity have been well characterized, including: ligand binding (intracellular and extracellular ligands), voltage sensitivity and phosphorylation of core channel subunits. However, proteolysis of core ion channel subunits by extracellular proteases is only recently gaining appreciation as an important regulatory mechanism governing ion-channel activity.
Cyclic nucleotide-gated (CNG) ion channels are members of the voltage-gated channel superfamily and are activated by the intracellular binding of cyclic nucleotides. CNG channels are expressed in a variety of tissues (e.g., neuronal, kidney, and vascular tissues) but are most notably involved in sensory transduction—particularly visual and olfactory transduction. We have recently demonstrated that CNG channel function can be influenced by members of a family of secreted endopeptidases, matrix metalloproteinases (MMPs), via proteolytic modification of CNGA subunits. For both heterologously expressed and native photoreceptor CNG channels, extracellular exposure to MMPs dramatically increased the sensitivity of these channels to their activating ligands (i.e., cGMP and cAMP). These findings highlighted potential extracellular control of channel ligand sensitivity. We are currently trying to address the following questions: 1) What is the mechanistic basis by which MMP-directed proteolysis increases the ligand sensitivity; 2) What is the physiological importance of this regulatory contribution to CNG channel function; and 3) Abnormal MMP expression has been associated with a variety of pathological conditions (e.g., neoplasm, stroke, macular degeneration)—does dysregulation of CNG channel function contribute to the pathogenesis of these conditions? We are addressing these questions with neurophysiological techniques (patch clamping, field potential recordings), and biochemical and computational approaches.
Peter Meighan, Ph.D. received his B.S. in Philosophy from Washington State University in 2000. He then went on to complete his Ph.D. in Neuroscience also from Washington State University in 2006. His research career has primarily taken place at Washington State University as a graduate teaching assistant, instructor in the IPN department, and as an undergraduate advisor for the Neuroscience program. He is now a clinical assistant professor at WSU.