PLATELET ALPHA 2 RECEPTORS--MODELS FOR EFFECTOR COUPLING

Project: Research project

Description

The vast majority of synaptic transmission in the mammalian nervous system
is mediated by neurotransmitter messengers. Propagation of this
information depends upon the transfer of the stimulus from the receptor to
intracellular effectors. The hormonal stimulation of adenylate cyclase
activity is a model system of receptor-effector coupling that has been
studied extensively. Until recently, however, much less attention has been
directed toward hormonal inhibition of adenylate cyclase and the related
effects of guanyl nucleotides on the receptor binding of agonists. Recent
studies in many laboratories have suggested that separate regulatory
subunits mediate the stimulatory and inhibitory hormonal regulation of
adenylate cyclase (Ns and Ni respectively) and that there may also be a
separate subunit for the regulation of the binding of agonists. In a
series of studies in intact human platelets, we have found the regulation
of the binding of alpha2 agonists to be functionally dissociated from the
inhibition of adenylate cyclase that is produced by these agonists.
Additionally, maximal inhibition of adenylate cyclase occurs at low levels
of occupancy of alpha2-adrenergic receptors. This finding is reminiscent
of studies in stimulatory systems, and we have obtained direct evidence for
the presence of spare receptors in our system. In the present grant
period, I expect to further characterize the agonist-subpopulations of
alpha2 adrenergic receptors of intact platelets by pharmacological and
bichemical means to determine: (1) whether the subpopulations are readily
interconverted in the absence of guanyl nucleotides; and (2) which
subpopulation(s) is related to the inhibition of adenylate cyclase. The
findings from these studies may have relevance to other receptor systems
which are inversely coupled to adenyate cyclase. Additionally, a
concurrent computer-simulation of spare receptor theory will provide
theoretical guidelines to the study of the receptor reserve of intact
platelets; in turn, the experimental study will provide empirical
guidelines for the simulation. Recent clinical investigations in our
laboratory, as well as others, have examined the alpha2 adrenergic receptor
in the platelet as a biological marker in major depressive disorders. The
studies described in this proposal will increase our understanding of
alpha2 receptors in the platelet and will contribute to complex and novel
approaches to the use of platelet alpha2 receptors as biological markers in
clinical studies of neuropsychiatric disease.
StatusFinished
Effective start/end date4/1/849/30/87

Funding

  • National Institutes of Health
  • National Institutes of Health

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Blood Platelets
Adenylyl Cyclases
Adrenergic Receptors
Nucleotides
Biomarkers
Major Depressive Disorder
Synaptic Transmission
Computer Simulation
Adrenergic Agents
Neurotransmitter Agents
Pharmacology
Guidelines
Inhibition (Psychology)