Molecular and cell-specific alpha-2 adrenergic receptor signal transduction

Abstract

Alpha-2 adrenergic receptors (α₂-ARs) were originally identified as pre-junctional receptors which inhibit neurotransmitter release. However, it is clear that α₂-ARs are not only pre-junctional receptors but are found on many effector organs and cells such as platelets and smooth muscle and are responsible for numerous functions including the central control of blood pressure, nociception and lipolysis. Three subtypes of α₂-AR have been identified in the human by molecular cloning as α₂A, α₂B and α₂C. This makes possible the study of individual subtypes in recombinant systems as well as the production of subtype-specific antibodies. Using these tools, molecular and cell-specific α₂-AR signal transduction was studied. Species homologues, unique structural characteristics, co-expression of receptor subtypes and endogenous α₂-ARs were investigated for their effects on signal transduction. Despite the unique pharmacology of the guinea pig atria, the α₂-ARs homologues interact with a cAMP-responsive reporter gene in the same manner as the human subtypes. Mutation of unique structural characteristics in the carboxy terminus and the seventh transmembrane domain of the α₂C AR, indicates that these regions are essential to receptor signal transduction and ligand binding and that there is a communication between the carboxy terminus and the seventh transmembrane domain of the receptor. Subtypes of α₂-AR co-expressed in a recombinant system were mostly inhibitory to cAMP production unlike singly expressed α₂-AR subtypes. Endogenous α₂-ARs generally decrease cAMP levels, indicating that co-expression may be common. The relatively biphasic nature of all co-expressed receptor combinations indicates that there is some redundancy of α₂-AR subtype function. Furthermore, it was found that fetal rat myocytes co-express α₂A and α₂C which inhibit cAMP production and increase actin cytoskeleton arrangement. Rat alveolar macrophages also co-express α₂A and α₂C which activate the mitogen-activated protein kinase pathway. It is only through an understanding of the molecular structure and signal transduction of the individual subtypes of α₂-ARs that selective drugs can be developed. It is the goal of this work to add to the knowledge of α₂-AR subtype structure and function through characterization of molecular and cell-specific α₂-AR signal transduction.