Responsiveness to hormone signals is actively regulated in various normal physiological states as well as disease states. In regard to adrenergic responses there may be spontaneous hypersensitivity (as in glucocorticoid exposure), spontaneous hyposensitivity (as in asthma), or acquired hyposensitivity (as in chronic catecholamine exposure or metabolic acidosis). Examinations of these illnesses as well as corresponding animal models have shown that adrenergic responsiveness may be modified by altering receptor number or affinity, receptor interactions with guanine-nucleotide regulatory proteins (G-proteins) including the formation of a high affinity form of the receptor, or other biochemical altercations. In the dysautonomia of mitral valvular prolapse (MVP) dysautonomia), increased catecholamine responsiveness is associated with increased formation of a high affinity, """"""""activated"""""""" form of the receptor. This greater formation of the high affinity state of the receptor is related to a functional alteration in Gs in these individuals. In contract, the decreased catecholamine responsiveness of chronic agonist exposure is associated with diminished formation of the high affinity state of the receptor. There may be alterations in stimulatory G-proteins (Gs) or inhibitory G-proteins (Gi) independent of receptor alterations. The purpose of the current effort is to comprehensively examine these regulatory processes involving of both beta 2-adrenergic receptors and G-proteins in these illnesses. Particular focus will be upon regulation in MVP dysautonomia since it is a unique form of regulation without a currently recognized animal mode. In MVP dysautonomia there is an abnormal propensity to desensitize upon catecholamine exposure, so the mechanism of desensitization in MVP dysautonomia will be examined. The specific hypotheses to be tested in this proposal are: 1) that genetically abnormal G-proteins result in disordered signal transduction, which in turn causes the clinical an physiological manifestations of the MVP dysautonomia; and 2) that the enhanced desensitization in MVP dysautonomia is a consequence of greater high affinity state formation with greater activation of desensitization processes rather than intrinsic abnormalities those processes themselves.
| Davies, A O; Su, C J; Balasubramanyam, A et al. (1991) Abnormal guanine nucleotide regulatory protein in MVP dysautonomia: evidence from reconstitution of Gs. J Clin Endocrinol Metab 72:867-75 |
