Neuronal plasticity is a general feature prevalent among functions as diverse as memory, movement, and pain. Therefore, fundamental research into mechanisms of plasticity has the potential for profound contributions to key questions of high medical and scientific impact, especially in the study of peripheral pain. Although pain disorders carry a large financial burden to society and the health care system, this is superseded by an incalculable loss in quality of life due to persistent peripheral pain. In this application, we address this issue by focusing on activity-dependent changes at the level of the primary afferent neuron that occur in response to various types of injury, including chronic, neuropathic and inflammatory. Peripheral plasticity, the modification/ modulation of proteins present at peripheral afferent terminals, highlights the transition from normal, neuronal signaling pathways into hypersensitive, nociceptive transducers of persistent, painful states. Recently, the study of nociceptive signaling has included the examination of receptor-channels and the modulatory biochemical and cellular mechanisms that control receptor-channel activity. The TRPV1 family of Transient Receptor Potential (TRP) receptor-channels serves as a principal member for the study of peripheral pain perception, as it has been examined extensively and is expressed on a subset of non-myelinated, C-type neurons that transmit painful stimuli (nociceptors). Post- translational modifications of TRPV1 in response to injury, including phosphorylation, significantly alter channel activity, and thereby affect the plasticity of the system. Recently, we have demonstrated that certain TRPV1 phosphorylation events are functionally dependent upon the scaffolding protein A-Kinase Anchoring Protein (AKAP). Initially, AKAP was characterized as solely mediating Protein Kinase A (PKA) phosphorylation of substrates, although recent evidence indicates that AKAP also associates with PKC and directs its signaling pathway as well. In this application, we propose to test the primary hypothesis that AKAP organizes the post- translational phosphorylation of TRPV1. To accomplish this, we will first evaluate whether alterations in AKAP150 association with Protein Kinase C (PKC) leads to alterations in TRPV1 phosphorylation and sensitization of TRPV1 channel activity. Second, we will evaluate whether receptor-activation of PKC requires AKAP150 to alter TRPV1 phosphorylation and sensitization of TRPV1 channel activity. Thirdly, we will determine whether AKAP150 modulates TRPV1 activity via PKA and PKC in vivo. Validation of our hypothesis will stimulate future endeavors to investigate how AKAP-organized modifications of TRPV1 phosphorylation by PKA can be selectively controlled in clinically relevant situations to relieve peripheral pain. PUBLIC HEALTH RELEVACNE Fundamental research into mechanisms of neuronal plasticity has the potential for profound contributions to key questions of high medical and scientific impact in the study of pain. Although pain disorders carry a large financial burden to society and the health care system, this is superseded by an incalculable loss in quality of life due to persistent pain. In this application, we address this issue by determining the role of the scaffolding protein AKAP in modulating the sensitization of pain-sensing neurons in the periphery, to inspire the generation of new drugs that will inhibit pain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS061884-04
Application #
8099576
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Babcock, Debra J
Project Start
2008-07-01
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2011
Total Cost
$318,347
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Dentistry
Type
Schools of Dentistry
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
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Rowan, Matthew P; Bierbower, Sonya M; Eskander, Michael A et al. (2014) Activation of mu opioid receptors sensitizes transient receptor potential vanilloid type 1 (TRPV1) via ?-arrestin-2-mediated cross-talk. PLoS One 9:e93688
Por, Elaine D; Gomez, Ruben; Akopian, Armen N et al. (2013) Phosphorylation regulates TRPV1 association with ?-arrestin-2. Biochem J 451:101-9
Jeske, Nathaniel A (2012) Somatosensory scaffolding structures. Front Mol Neurosci 5:2
Por, Elaine D; Bierbower, Sonya M; Berg, Kelly A et al. (2012) ?-Arrestin-2 desensitizes the transient receptor potential vanilloid 1 (TRPV1) channel. J Biol Chem 287:37552-63
Jeske, Nathaniel A; Por, Elaine D; Belugin, Sergei et al. (2011) A-kinase anchoring protein 150 mediates transient receptor potential family V type 1 sensitivity to phosphatidylinositol-4,5-bisphosphate. J Neurosci 31:8681-8
Gomez, Ruben; Por, Elaine D; Berg, Kelly A et al. (2011) Metallopeptidase inhibition potentiates bradykinin-induced hyperalgesia. Pain 152:1548-54
Chaudhury, Sraboni; Bal, Manjot; Belugin, Sergei et al. (2011) AKAP150-mediated TRPV1 sensitization is disrupted by calcium/calmodulin. Mol Pain 7:34
Rowan, Matthew P; Berg, Kelly A; Milam, Stephen B et al. (2010) 17beta-estradiol rapidly enhances bradykinin signaling in primary sensory neurons in vitro and in vivo. J Pharmacol Exp Ther 335:190-6
Por, Elaine D; Samelson, Bret K; Belugin, Sergei et al. (2010) PP2B/calcineurin-mediated desensitization of TRPV1 does not require AKAP150. Biochem J 432:549-56

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