Molecular mechanisms of store-operated calcium channels in pain

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DESCRIPTION (provided by applicant): Chronic pain continues to be a major public health concern with considerable effort directed towards achieving a better understanding of the underlying mechanisms to facilitate the development of more effective and safer therapeutics. The research in my lab focuses on the role of store-operated calcium channels (SOCCs) in the modulation of pain. SOC channels are composed of recently discovered Orai subunits (Orai1/2/3, pore-forming subunits), and stromal interaction molecules (STIM) 1 and STIM2 (the ER Ca2+ sensors, serve as their activators). Activation of SOCCs by the release of calcium from endoplasmic reticulum (ER) leads to sustained high levels of cytosolic Ca2+ that are required for many calcium-dependent cellular processes. In the central nervous system (CNS), SOC channels are known to influence neurotransmitter release and synaptic plasticity. Results from our current R21 grant have demonstrated that SOCCs are functionally expressed in dorsal horn neurons and their pharmacological properties are similar to those in non-excitable cells. We have identified STIM1 and Orai1 as essential components of SOCCs in dorsal horn neurons and have demonstrated that the knockdown of STIM1 and Orai1 proteins individually reduces spare nerve injury (SNI)-induced neuropathic pain. Recently, we found that the SOC inhibitor YM- 58483 not only attenuates neuropathic pain, but also dramatically diminishes inflammatory pain. Of interest is the finding that a SOCC inhibitor blocks NMDA and mGluR1/5 agonist- induced sustained calcium entry and nociceptive behavior at later time points, suggesting that SOCCs are involved in functions of NMDA receptors and mGluR1/5. Based on these findings, we hypothesize that SOCC involvement in pain is mediated by their interaction with NMDA receptors and mGluR1/5. To test this hypothesis, we will combine the methods of patch-clamp recording, calcium imaging recording, Western Blot analysis and behavioral testing. Overall, our long-term goal is to understand the mechanisms of chronic pain. The goals of this proposal are to identify endogenous upstream molecules of SOCC signaling and explore functional consequences of SOCC activation. These studies will extend our knowledge of how the SOCC signaling modulates pain. Our findings will establish functional links between SOCCs and group I mGluR, and between SOCCs and NMDA receptors. These studies will provide novel insights into mechanisms of pain and other CNS disorders and may suggest new approaches to therapeutic intervention.