Aging is generally associated with altered adrenergic responsiveness. Many of the adrenergic responses are mediated primarily through the regulation of adenylate cyclase activity in the plasma membrane. Beta-adrenergic receptors mediate the stimulation of adenylate cyclase, whereas Alpha2-adrenergic receptors inhibit the enzyme. Beta-adrenergic mediated stimulation of adenylate cyclase activity has generally been observed to decline in old age, while Alpha2-adrenergic regulation of adenylate cyclase has not been examined as a function of aging. Increasing awareness of the molecular events involved in both the stimulation and inhibition of adenylate cyclase now allows a detailed examination to be made of possible alterations in various steps in the transduction of adrenergic stimuli, which are associated with aging. The present project proposes to examine the Beta-adrenergic stimulated adenylate cyclase activity of the myocardium of young and aged rats and the polymorphonuclear leukocytes of young and old humans, in terms of the efficiency of coupling between hormone receptors, stimulatory guanine nucleotide regulatory protein and catalytic unit. The Alpha2-adrenergic inhibition of adenylate cyclase of the platelets of young and old human subjects will also be examined to determine whether there is any alteration in the coupling between the Alpha-adrenergic receptor, the inhibitory GTP regulatory protein and catalytic unit as a function of aging. Conditions will also be established which will allow the examination of the both Beta- and Alpha2-adrenergic regulation of the adenylate cyclase activity in rat cerebellum and hippocampus, respectively. These properties will then be compared in young and aged rats. Attempts will also be made to solubilize the GTP regulatory protein and catalytic unit of cerebellar cyclase in order to determine whether changes in these components occur which are independent of alterations in the general properties of the membrane. These studies should provide the first detailed examination of age-related changes in the adrenergic regulation of adenylate cyclase in terms of each of the coupling steps involved both in stimulation and inhibition of activity, and will allow speculations to be made as to whether the physiological changes in adrenergic responses associated with senescence might be accounted for by altered adenylate cyclase regulation.
| Caldwell, K K; Newell, M K; Cambier, J C et al. (1988) Evaluation of methods for the isolation of plasma membranes displaying guanosine 5'-triphosphate-dependence for the regulation of adenylate cyclase activity: potential application to the study of other guanosine 5'-triphosphate-dependent transduction syst Anal Biochem 175:177-90 |
