Many sympathetically-innervated tissues decrease their responsiveness after exposure to pharmacological levels of agonist. In contrast, physiological levels of sympathetic stimulation produced by cold exposure increase the responsiveness of adenylate cyclase in brown adipose tissue (BAT), a tissue in which catecholamines exert both trophic and metabolic actions. The research proposed here will investigate certain physiological and biochemical questions these findings raise. We will focus on the following specific issues: 1) Identification of the trans-synaptic signal that stimulates supersensitivity in BAT. 2) Investigation of the molecular basis of the supersensitivity, specifically by determining whether cold exposure alters guanine nucleotide-binding regulatory proteins in BAT membranes. 3) Evaluation of the functional significance of cold-induced supersensitivity by localizing the cell populations that contain supersensitive cyclase and determining its impact on the functioning of these cells. The phenomenon of neurally-mediated supersensitivity may be more widespread than is now recognized, but nevertheless remains poorly understood. The studies proposed will provide integrated information regarding the signals that initiate the supersensitive response, the molecular basis of it and its functional significance. In doing so we seek to define the conditions upon which the responsiveness of tissues to transmitters and drugs depends. Finally, these studies will provide basic knowledge about BAT, a tissue that has been implicated in the etiology of obesity.
| Granneman, J G; MacKenzie, R G (1988) Neural modulation of the stimulatory regulatory protein of adenylate cyclase in rat brown adipose tissue. J Pharmacol Exp Ther 245:1068-74 |
| Granneman, J G (1988) Norepinephrine infusions increase adenylate cyclase responsiveness in brown adipose tissue. J Pharmacol Exp Ther 245:1075-80 |
