Nociception, the process through which a subset of sensory neurons detects noxious (painful) stimuli, is an important but poorly understood process in the trigeminal ganglion neurons that innervate the cornea. These neurons respond to a wide array of irritating stimuli including heat, cooling, mechanical force, and chemicals including protons and inflammatory molecules. Inflammation in the cornea, a result of damage to the neurons that innervate it, often leads to sensitization of those neurons. The response to noxious stimuli and to inflammatory molecules is mediated in large part by ion channels, G-protein coupled receptors (GPCRs), and receptor tyrosine kinases (RTKs). A better understanding of the ion channels involved in ocular pain and the hyperalgesic sensory pathway would be important for development of more targeted pain management tools. It has been long known that the cornea displays a strong response to pH, but until recently, it was not known what molecule is responsible for sensing acidification. New work has identified the acid-sensing ion channels (ASICs) as the primary pH sensor. Moreover, there has been some suggestion that these channels can be sensitized in response to inflammation. The goal of this work is to understand the cellular and molecular mechanisms by which GPCRs and RTKs regulate the function, trafficking, and expression of acid-sensing on channels during pain transduction. To do this, I will record electrical signals from both from isolated corneal nerves and intact nerve terminals. I will measure the ion channels response to pro-inflammatory molecules like kinins and prostaglandins. Many of these inflammatory molecules trigger the activation of the phospholipase c signaling pathway, which reduces the amount of the phosphoinositide, PI(4,5)P2, in the membrane. Change in PI(4,5)P2 has been shown to sensitize other channels to stimulation and I hypothesize that the same is happening for ASICs. Thus, I will examine the role that regulation of phosphoinositides play in corneal neurons and in the function of ASICs.
Little is understood about ocular pain, which can include, pain at the ocular surface, orbital pain, and referred pain. This proposal seeks to uncover the molecules responsible for sensing pain and responding to tissue inflammation during ocular injury or disease.
| Bankston, John R; DeBerg, Hannah A; Stoll, Stefan et al. (2017) Mechanism for the inhibition of the cAMP dependence of HCN ion channels by the auxiliary subunit TRIP8b. J Biol Chem 292:17794-17803 |
