The goal of our work is to elucidate the cellular and molecular mechanisms by which cell-surface receptors regulate the function, trafficking, and expression of ion channels. We are particularly interested in receptor regulation of ion channels in pain transduction, as sensitization to painful stimuli during inflammation (inflammatory hyperalgesia) profoundly influences our physical and mental health, as well as our economic and social well-being. We have chosen the Ca2+-permeable channel TRPV1 as our model both because its properties make it especially suitable and because of its importance in transducing painful stimuli and in tuning the excitability of pain-transducing neurons. Chronic pain is a significant public health and economic problem in the US. An analysis of the 2003 American Productivity Audit, a national survey of US workers, showed that, in a given two-week period, 13% of the workforce lost work time due to uncontrolled pain, with a mean loss of 4.6 hours per week. The 2003 National Center for Health Statistics Report found that 26% of adults report having a problem with pain lasting more than 24 hours. A 2006 study of chronic pain patients found that more than half felt they had little or no control over their pain. Headache, back pain, arthritis pain, tooth pain, cancer pain, and post-operative pain are just a few of the common conditions contributing to decreased quality of life and economic loss across the whole spectrum of the US population. Current treatments are clearly not sufficient to address the wide-spread need for pain relief, and have further problems related to specificity and addiction. Nerve Growth Factor (NGF) was discovered by Rita Levi-Montalcini and Stanley Cohen in the late 1950's. From the first, they understood its power to regulate the differentiation and growth of sensory neurons. NGF is involved in the guidance and survival of sensory neurons and is released onto TRPV1-expressing neurons during injury and inflammation. Our understanding of how NGF sensitizes TRPV1 in inflammatory hyperalgesia exploded in the last several years. In the previous funding period we showed that NGF increases TRPV1 currents by increasing the number of the TRPV1 channels in the plasma membrane. We further showed that a signal-transduction complex is present in nociceptors, composed of the NGF receptor (TrkA), TRPV1, and the enzyme PI3K, which phosphorylates phosphoinositide 4,5-bisphosphate (PIP2) to phosphoinositide 3,4,5-trisphosphate (PIP3). We and others further showed that PI3K activity is required for sensitization. For the remainder of this proposal use the term """"""""sensitization"""""""" of TRPV1 to refer to the increase in the number of TRPV1 channels in the plasma membrane. Although cell surface receptor-stimulated trafficking of membrane lipids and membrane proteins is of broad significance to biology, the molecular mechanisms by which it occurs are poorly understood. One of the best-studied examples, trafficking of the Glut4 glucose transporter to the plasma membrane of adipocytes and muscle cells in response to insulin, has revealed a number of important players on which we based our model for NGF-induced trafficking of TRPV1 to the plasma membrane of pain-receptor neurons. Even in adipocytes and muscles, however, many critical steps in this process are not fully understood. Identification of the main players and their interactions in sensitization of TRPV1 may shed light on a signaling pathway essential to cell differentiation, metabolism, and survival in addition to leading to an understanding of TRPV1 regulation important for inflammatory pain.

Public Health Relevance

Cell surface receptors regulate the sensitivity of pain receptor cells in the cornea and throughout the periphery. We will investigate the mechanisms by which the sensitivity of pain receptors is increased by the interaction of inflammatory factors with cell surface receptors.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
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Araj, Houmam H
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University of Washington
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Gordon, Sharona E; Munari, Mika; Zagotta, William N (2018) Visualizing conformational dynamics of proteins in solution and at the cell membrane. Elife 7:
Stratiievska, Anastasiia; Nelson, Sara; Senning, Eric N et al. (2018) Reciprocal regulation among TRPV1 channels and phosphoinositide 3-kinase in response to nerve growth factor. Elife 7:
Aman, Teresa K; Gordon, Sharona E; Zagotta, William N (2016) Regulation of CNGA1 Channel Gating by Interactions with the Membrane. J Biol Chem 291:9939-47
Zagotta, William N; Gordon, Moshe T; Senning, Eric N et al. (2016) Measuring distances between TRPV1 and the plasma membrane using a noncanonical amino acid and transition metal ion FRET. J Gen Physiol 147:201-16
Gordon, Sharona E; Senning, Eric N; Aman, Teresa K et al. (2016) Transition metal ion FRET to measure short-range distances at the intracellular surface of the plasma membrane. J Gen Physiol 147:189-200
Rosasco, Mario G; Gordon, Sharona E; Bajjalieh, Sandra M (2015) Characterization of the Functional Domains of a Mammalian Voltage-Sensitive Phosphatase. Biophys J 109:2480-2491
Senning, Eric N; Gordon, Sharona E (2015) Activity and Ca²? regulate the mobility of TRPV1 channels in the plasma membrane of sensory neurons. Elife 4:e03819
Ufret-Vincenty, Carmen A; Klein, Rebecca M; Collins, Marcus D et al. (2015) Mechanism for phosphoinositide selectivity and activation of TRPV1 ion channels. J Gen Physiol 145:431-42
Gordon, Sharona E (2014) Getting nowhere fast: the lack of gender equity in the physiology community. J Gen Physiol 144:1-3
Gordon, Sharona E (2014) Restoring integrity to the scientific literature: lowering the bar to raise our standards. J Gen Physiol 144:495-7

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