DESCRIPTION (provided by applicant): Neuropathic pain represents a clinical challenge for the practicing physician and is a great burden to society. Although the mechanisms underlying neuropathic pain remain to be established, calcium-permeable ion channels and receptors have been implicated in pain as well as in the neuroplasticity associated with chronic pain states. Store-operated calcium (SOC) channels are highly Ca2+-selective cation channels that are activated by the release and depletion of calcium from the endoplasmic reticulum. Activation of SOC channels leads to sustained high cytosolic Ca2+ levels that are required for many calcium-dependent cellular processes. SOC channels are composed of newly 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) in non-excitable cells. In the nervous system, SOC channels are known to influence neurotransmitter release and synaptic plasticity. STIM2 is essential for ischemia-induced cytosolic Ca2+ accumulation in neurons, but the basic properties of SOC channels and molecular components underlying SOC channels in neurons are unexplored. Recently, we found that SOC channels are functionally expressed in spinal dorsal horn neurons and demonstrated that activation of SOC channels is involved in synaptic transmission. These observations raise questions as to the function of SOC channels and to the nature of the signaling pathways that are coupled to the activation of these channels in pain signal transmission. We also found that the expression of the SOC channels is upregulated at different time points after spare nerve injury (SNI). Based on these findings, we hypothesize that the SOC channels may play a role in neuronpathic pain. To test our hypothesis, we will combine the methods of patch-clamp recording, calcium imaging recording, Taqman real-time-PCR and behavioral testing. Overall, our long-term goal is to identify key molecular targets involved in chronic pain. The goals of this proposal are to determine basic properties of SOC channels, to identify molecules encoding SOC channels in dorsal horn neurons, and to determine the role of SOC channel family in neuropathic pain. The expected outcome of this research is the identification of new calcium signaling in pain pathway and a new mechanism underlying the development and maintenance of neuropathic pain. PUBLIC HEALTH RELEVANCE: Store-operated calcium (SOC) channels are activated by the release and depletion of calcium, are expressed in spinal dorsal horn neurons and, based on preliminary studies in our laboratory, appear to play a role in pain. The primary objective of this proposal is to identify the molecular components of SOC channels and to explore the definitive role of the SOC channel family in neuropathic pain with a view towards identifying new therapeutic targets.
|Effective start/end date||6/1/12 → 5/31/14|
- National Institutes of Health: $231,750.00
- National Institutes of Health: $186,366.00