Room: VBR 360
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.
- Meighan SE, Meighan PC, Choudhury P, Davis CJ, Olson ML, Zornes PA, Wright JW, Harding JW (2006) Effects of extracellular matrix-degrading proteases matrix metalloproteinases 3 and 9 on spatial learning and synaptic plasticity J Neurochem 96(5), 1227-1241 PMID: 16464240
- Davis CJ, Kramár EA, De A, Meighan PC, Simasko SM, Wright JW, Harding JW (2006) AT4 receptor activation increases intracellular calcium influx and induces a non-N-methyl-d-aspartate dependent form of long-term potentiation Neuroscience 137(4), 1369-1379 PMID: 16343778
- Meighan PC, Meighan SE, Davis CJ, Wright JW, Harding JW (2007) Effects of matrix metalloproteinase inhibition on short- and long-term plasticity of Schaffer collateral/CA1 synapses J Neurochem 102(6), 2085-96 PMID: 17587312
- Phillips DJ, Schei JL, Meighan PC, Rector DM (2011) State-dependent changes in cortical gain control as measured by auditory evoked responses to varying intensity stimuli Sleep 34(11), 1527-37 PMID: 22043124 PMCID: PMC3198208
- Phillips DJ, Schei JL, Meighan PC, Rector DM (2011) Cortical evoked responses associated with arousal from sleep Sleep 34(1), 65-72 PMID: 21203374 PMCID: PMC3001797
- Meighan PC, Meighan SE, Rich ED, Brown RL, Varnum MD (2012) Matrix metalloproteinase-9 and -2 enhance the ligand sensitivity of photoreceptor cyclic nucleotide-gated channels Channels (Austin) 6(3), 181-96 PMID: 22699690 PMCID: PMC3431585
- Meighan SE, Meighan PC, Rich ED, Brown RL, Varnum MD (2013) CNG channel subunit glycosylation regulates MMP-dependent changes in channel gating Biochemistry 52(46), 8352-62 PMID: 24164424 PMCID: PMC4657727
- Meighan PC, Peng C, Varnum MD (2015) Inherited macular degeneration-associated mutations in CNGB3 increase the ligand sensitivity and spontaneous open probability of cone cyclic nucleotide-gated channels Front Physiol 6, 177 PMID: 26106334 PMCID: PMC4460308