Calcium dependent regulation of brain and cardiac muscle adenylate cyclase.

The very close interdependence of Ca2+ and hormones in the overall metabolism of cyclic nucleotides has recently been emphasized by Cheung. Clearly the results presented here show that [Ca2+] in the physiological range (less than 10(-7) M to greater than 10(-6) M) has profound effects on the activity of adenylate cyclase from both brain and cardiac muscle. Whereas both brain and cardiac cyclase exhibit a Ca2+ dependent inhibition (perhaps mediated by calmodulin), only the brain cyclase is activated by Ca2+ via calmodulin. With both cyclases there is an inverse relationship between the inhibition of cyclase and the activation of calmodulin dependent (cAMP and cGMP) phosphodiesterase as a function of Ca2+ concentration. Because the IC50's for Ca2+ are the same in both heart and brain, the possibility exists that the Ca2+ inhibitory site of both cyclases is similar and perhaps identical. Considering the ability of Ca2+ to both stimulate and inhibit cyclase, one could imagine that in different species, tissues, or regions of the same tissue, there could exist multiple populations of cyclase, that is a cyclase which would only show Ca2+ dependent inhibition, Ca2+ dependent stimulation, or the biphasic response to Ca2+ (FIGURE 7). The fact that Ca2+ still regulates adenylate cyclase after various stimuli (histamine, NaF, etc.) suggests that Ca2+ may function to regulate the cyclase over shorter time periods (regardless of its state of stimulation) and that other affectors of cyclase (e.g., hormones) would serve to regulate the cyclase over longer time periods.

Signal transduction by G proteins in cardiac tissues.

The role of G proteins in mediating the responses of the heart to circulating catecholamines and to the influences of the autonomic nervous system is of special interest to cardiologists. It is evident that G proteins are essential links in the cascade of biochemical events that ensure when neurotransmitters and hormones interact with receptors on myocardial cells. It is likely [corrected] that dysfunction of G proteins plays a role in cardiovascular pathophysiology. With current methodologies, especially molecular biological and recombinant DNA techniques, and with transgenic animal models that can relate physiological function and specific gene dosage, some cardiovascular diseases may be traced to G protein-related defects.

Mechanisms of denervation supersensitivity in regionally denervated canine hearts.

Mechanisms responsible for "denervation supersensitivity" in regionally denervated canine hearts were examined by measuring beta-adrenergic receptor density and affinity and the density of the alpha-subunit of the stimulatory G protein (Gs alpha). Sympathetic denervation was produced by applying an epicardial strip of phenol midway between the left ventricular (LV) base and apex. Six to eight days after denervation, dogs were anesthetized and then underwent functional studies (n = 4) or hearts were excised for biochemical analyses (n = 6). Biochemical studies were also done on 3 nondenervated hearts. Effective refractory periods (ERPs) were measured in innervated (base) and denervated (apex) LV myocardium. During sympathetic stimulation (2 and 4 Hz), the ERP shortened more (P < 0.05) at basal than at apical sites, whereas during norepinephrine infusion (0.05 to 0.5 mg.kg-1 x min-1), the ERP shortened more (P < 0.001) at apical than at basal sites. In regionally denervated hearts, however, the density and affinity of beta-adrenergic receptors did not differ significantly (P > 0.2) in nondenervated basal compared with denervated apical myocardium. Quantitative immunoblotting of the Gs alpha demonstrated that the density of the 47- and 52-kDa subunits was also similar (P > 0.6) in basal compared with apical myocardium from regionally denervated hearts. In addition, beta-adrenergic receptor density and affinity and Gs alpha density did not differ significantly (P > 0.5) in basal compared with apical myocardium from nondenervated control hearts.(ABSTRACT TRUNCATED AT 250 WORDS)