The long-term objective of this proposal is to understand how opioid receptors, present in rat sympathetic stellate ganglion (SG) neurons innervating the heart, couple to calcium channels involved in neurotransmitter release. This project will focus on a newly identified opioid receptor (OP4) that is activated by nociceptin (NOC). Noc-mediated OP4 receptor activation elicits cardiovascular responses such as bradycardia and hypotension via pathways that influence the autonomic nervous system--mostly through an inhibition of neural transmission. A combination of etectrophysiological, molecular, optical and biochemical techniques will be used to probe the mechanisms whereby Noc-activated OP4 receptors modulate N-type calcium channels.
The specific aims of the proposal are to: (i) identify the specific Galpha subunit that couples OP4 receptors to N-type calcium channels; (ii) examine the kinetic role which regulators of G protein signaling (RGS) proteins play in Noc-mediated calcium channel inhibition; (iii) investigate whether OP4 receptors are capable of forming homo- or hetero-oligomers. OP4 receptors play an important role in the autonomic nervous system pathways that contribute to heart rate and blood pressure regulation. The proposed studies will help to clarify the signaling mechanisms underlying these processes and facilitate the development of novel cardiovascular agents for treating hypertension resulting from increased sympathetic tone. Moreover, the information gathered from these studies may help determine the precise role opioids play in decreasing myocardial infarct size. ? ? ?
