Chemical and thermal pain in the cornea is primarily transduced by a calcium- and sodium-permeable ion channel called TRPV1 expressed in nociceptors with cell bodies in the trigeminal ganglia. When injury (including surgery) or illness cause inflammation, the inflammatory process increases the sensitivity of TRPV1 ion channels to painful stimuli, a phenomenon known as inflammatory hyperalgesia. Our long-term goal is to understand the molecular mechanisms mediating inflammatory hyperalgesia, a critical first step in developing more effective pain therapies for corneal injury. In this study, we will focus on the molecular mechanisms of TRPV1 modulation by Nerve Growth Factor (NGF). Inflammation and injury lead to release of trophic factors such as NGF, insulin, and Insulin-like Growth Factor, which increase nociceptor excitability by activating receptor tyrosine kinases (RTKs). It has been proposed that RTK activation sensitizes TRPV1 through hydrolysis of phosphoinositide 4,5-bisphosphate (PIP2), relieving a tonic inhibition of TRPV1 by PIP2. The role of PIP2 is controversial, however, due to emerging evidence that phosphoinositide 3,4,5- trisphosphate (PIPS) may be involved. Based on our preliminary data, we propose that phosphorylation of PIP2 by phosphoinositide 3-kinase (PI3K) to form PIP3 may be an essential element of nociceptor sensitization by NGF.
Our specific aims will address the molecular mechanism and functional significance of TRPV1 modulation by NGF. Understanding the regulation of TRPV1 by RTKs is critical to a complete understanding of how inflammation modulates corneal nociceptor excitability and to the development of improved therapies to treat inflammatory pain.

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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Shen, Grace L
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University of Washington
Schools of Medicine
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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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