The long-term goal of this research project is to understand the role of scaffolding proteins in the regulation of nociceptor plasticity. Dynamic changes to proteins expressed in primary afferent terminals significantly alter pain sensation. For instance, ion channel phosphorylation can modulate channel activity, thereby affecting acute nocifensive responses to noxious stimuli. However, states of persistent pain likely rely on multiple mechanisms of dynamic protein modifications to maintain peripheral nociceptor sensitization. Therefore, nociceptor plasticity at the sensory terminal may exist to support persistent pain sensation. A large gap in knowledge exists concerning how neuroplastic changes in primary afferent neurons are integrated to contribute to the development of persistent pain. This represents an important unmet need, since the careful identification of molecular coordinators of persistent pain would provide new, peripheral therapeutic targets for analgesic drug development. The overall objective of this application is to identify that the development of persistent pain depends on autocrine nociceptor sensitization through a feed-forward, neuroplastic mechanism coordinated by A-Kinase Anchoring Protein 79/150 (AKAP). The central hypothesis for this application is that the scaffolding protein A-Kinase Anchoring Protein 79/150 (AKAP) coordinates nociceptor plasticity. This hypothesis will be addressed through three specific aims that (1) evaluate AKAP as an important coordinator of TRP channel sensitivity in cellular and behavioral models, (2) evaluate AKAP-dependence of feed-forward nociceptor sensitization, and (3) examine neuroplastic transcriptional control of AKAP expression. AKAP scaffolding mechanisms will be investigated through a combination of genetic, molecular, biochemical, behavioral and electrophysiology methods. The contribution of this research is significant because it is the first step towards developing novel peripherally active analgesics targeted at a key scaffolding mechanism of nociceptor plasticity. Research results will demonstrate that disrupting the scaffolding protein AKAP can significantly undermine neuroplastic changes in nociceptor excitability that contribute to the development of many clinical pain states.
The proposed research is relevant to public health because the identification of scaffolding proteins as coordinators of nociceptor plasticity will provide a new target for preventative and therapeutic intervention in the treatment of pain. Once such strategies are possible, there is promise that persistent pain will be treated with local drugs targeted at nociceptor scaffolding mechanisms, minimizing detrimental side effects observed with current systemic analgesics such as opioids. The project is relevant to NIH's mission because targeting AKAP scaffolding mechanisms may serve as an effective approach to treating pain.
|Brackley, Allison Doyle; Sarrami, Shayda; Gomez, Ruben et al. (2017) Identification of a signaling cascade that maintains constitutive ?-opioid receptor incompetence in peripheral sensory neurons. J Biol Chem 292:8762-8772|
|Brackley, Allison Doyle; Gomez, Ruben; Guerrero, Kristi A et al. (2017) A-Kinase Anchoring Protein 79/150 Scaffolds Transient Receptor Potential A 1 Phosphorylation and Sensitization by Metabotropic Glutamate Receptor Activation. Sci Rep 7:1842|
|Hallums, D P; Gomez, R; Doyle, A P et al. (2016) RAF Kinase Inhibitory Protein Expression and Phosphorylation Profiles in Oral Cancers. Clin Surg 1:|
|Brackley, Allison Doyle; Gomez, Ruben; Akopian, Armen N et al. (2016) GRK2 Constitutively Governs Peripheral Delta Opioid Receptor Activity. Cell Rep 16:2686-2698|
|Hargreaves, K M; Ruparel, S (2016) Role of Oxidized Lipids and TRP Channels in Orofacial Pain and Inflammation. J Dent Res 95:1117-23|
|Szteyn, Kalina; Rowan, Matthew P; Gomez, Ruben et al. (2015) A-kinase anchoring protein 79/150 coordinates metabotropic glutamate receptor sensitization of peripheral sensory neurons. Pain 156:2364-72|
|Eskander, Michael A; Ruparel, Shivani; Green, Dustin P et al. (2015) Persistent Nociception Triggered by Nerve Growth Factor (NGF) Is Mediated by TRPV1 and Oxidative Mechanisms. J Neurosci 35:8593-603|
|Weng, Hao-Jui; Patel, Kush N; Jeske, Nathaniel A et al. (2015) Tmem100 Is a Regulator of TRPA1-TRPV1 Complex and Contributes to Persistent Pain. Neuron 85:833-46|
|Szteyn, Kalina; Gomez, Ruben; Berg, Kelly A et al. (2015) Divergence in endothelin-1- and bradykinin-activated store-operated calcium entry in afferent sensory neurons. ASN Neuro 7:|
|Rowan, Matthew P; Szteyn, Kalina; Doyle, Allison P et al. (2014) ?-arrestin-2-biased agonism of delta opioid receptors sensitizes transient receptor potential vanilloid type 1 (TRPV1) in primary sensory neurons. Mol Pain 10:50|
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