It is now clear that there is a large family of different receptors for norepinephrine (NE) and epinephrine (EPI). At least 7 pharmacologically distinct adrenergic receptor subtypes (beta l-, beta 2-, beta3-, alpha 1a-, alpha1b-, alpha2a-, alpha2b-) have already been identified. However,little information is available on the importance of these subtypes in responses to transmitters. Since they often coexist on cells and have primary actions on the same second messenger systems, the net response to transmitter will often be determined by combined actions on multiple subtypes. Our major hypothesis is that NE and EPI cause their effects through simultaneous activation of many different receptor subtypes, and that these subtypes interact in complex ways to determine the net response of the cell. We propose to use primary cultures from one day old rat brain to characterize second messenger responses to individual subtypes, clarify their interactions, and determine how the cellular response to transmitter is controlled. The following specific aims will be addressed: 1. To determine the receptor subtypes involved in second messenger responses to NE and EPI. Alkylating agents and competitive antagonists will be used to isolate responses to individual subtypes. 2. To determine if simultaneous co-activation of particular subtypes have inhibitory, additive, potentiative or redundant effects on responses to other subtypes. 3. To determine whether chronic agonist exposure down-regulates each subtype independently, and whether responses to NE and EPI are increased or decreased. 4. To begin to determine whether each adrenergic receptor subtype activates a different signal transduction mechanism by examining the effect of various manipulations on responses to different subtypes. During the next project period we hope to clarify the functional roles and interactions of the different adrenergic receptor subtypes.
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