Gerry S. Oxford, Ph.D.
(Emeritus) Professor of Pharmacology & Toxicology
Ph.D., Emory University (1974)
Postdoctoral, Duke University (1974-76)
Regulation of Ion Channels and Receptors involved in Affective Disorders 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+, or 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 manifest multiple responses to different agonists at the same receptor subtype (termed functional selectivity). The second theme involves understanding the functional properties and biochemical regulation 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 neurotransmitter release from individual neurons.
The following projects are among those underway in our laboratory:
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, Kir3 channels, CaV2 channels, and ERK. 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 selective G-protein subunit complexes, receptor oligomerization, RGS proteins, and protein scaffolding. The outcomes are critical for informing GPCR drug discovery efforts to reduce false negative candidates.
Peripheral nociceptors become hypersensitized to sensory inputs following injury and inflammation. We are examining the signaling pathways linking inflammatory mediators (e.g. NGF, artemin, ATP) to post-translational sensitization of TRPV1 via kinases. We have found distinct pathways linking different receptors to enhancement of TRPV1 activity and subsequent elevation of afferent pain signals.
Calcitonin-gene related peptide (CGRP) is involved in sensory neuron pain signaling for both peripheral somatic sensation and headache (e.g. migraine), but little is known of how CGRP modifies signaling in the pain pathways. We have found that CGRP can be released from sensory neuron cell bodies and elicits an excitatory response on those same neurons. In collaboration with Dr. Joyce Hurley, we have recently found evidence for trigeminal intraganglionic transmission in inhaled irritant induced headache-related responses. Our hypothesis is that CGRP is a paracrine/autocrine signal involved in maintaining sensitization of pain-related sensory neurons at the ganglionic level. Furthermore, this novel signaling regime may explain instances of “referred pain” between two distant sensory receptive fields.
Kunkler PE, Ballard CJ, Oxford GS, Hurley JH. TRPA1 receptors mediate environmental irritant-induced meningeal vasodilatation. Pain 152(1):38-44, 2011.
Brittain JM, Duarte DB, Wilson SM, Zhu W, Ballard C, Johnson PL, Liu N, Xiong W, Ripsch MS, Wang Y, Fehrenbacher JC, Fitz SD, Khanna M, Park CK, Schmutzler BS, Cheon BM, Due MR, Brustovetsky T, Ashpole NM, Hudmon A, Meroueh SO, Hingtgen CM, Brustovetsky N, Ji RR, Hurley JH, Jin X, Shekhar A, Xu XM, Oxford GS, Vasko MR, White FA, Khanna R. Suppression of inflammatory and neuropathic pain by uncoupling CRMP-2 from the presynaptic Ca²? channel complex. Nature Medicine 17(7):822-829, 2011.
Zhu W, Oxford GS. Differential gene expression of neonatal and adult DRG neurons correlates with the differential sensitization of TRPV1 responses to nerve growth factor. Neurosci Lett. 500(3):192-196, 2011.
Molosh AI, Sajdyk TJ, Truitt WA, Zhu W, Oxford GS, Shekhar A. NPY Y1 receptors enhance overall inhibition of basolateral amygdala neurons by differentially modulating GABAA and NMDA receptors through divergent signal transduction pathways. Neuropsychopharmacology 38(7):1352-1364, 2013.
Oxford GS and Hurley JH. The role of TRP channels in migraine. Open Pain Journal 6:37-49, 2013.
Kunkler PE, Ballard CJ, Pellman JJ, Zhang LJ, Oxford GS, Hurley JH. Intraganglionic signaling as a novel nasal-meningeal pathway for TRPA1-dependent trigeminovascular activation by inhaled environmental irritants. PLoS ONE 9:e103086, 2014.