The mode of the inhibition of purified rat brain adenylate cyclase by the beta gamma-subunits of G protein (beta gamma) was studied. These subunits inhibited the catalytic activity of the cyclase with the maximal inhibition of 85% and the half-maximal inhibition at about 0.7 nM beta gamma. The complex of beta gamma and adenylate cyclase isolated by density gradient centrifugation contained 1.8-2.0 mol beta gamma per mol of the cyclase when beta gamma was assayed by immunoblotting and by its inhibitory activity on adenylate cyclase. However, the beta gamma concentration-inhibition curves suggest that one of the two beta gamma molecules bound may be essential for the inhibition. The role for the second beta gamma molecule is unknown. As a tentative estimate, 70% of the adenylate cyclase activity remained inhibited by beta gamma when the complex was isolated. The inhibition was not dependent on G alpha s or calmodulin. Although purified adenylate cyclase contained a protein (0.06-0.08 mol/mol of adenylate cyclase) that reacted with anti-G alpha s antibody, this protein was not liberated from the cyclase when it formed a complex with beta gamma. In addition, guanine nucleotide analogs little affected the cyclase activity or the inhibition by beta gamma. The inhibition by beta gamma was reversed by the dilution of the complex, and the following re-addition of beta gamma suppressed the enzyme activity to about 15% of the initial activity again. These findings provide strong evidence that beta gamma inhibits adenylate cyclase directly and reversibly through the formation of the complex.

Adenylyl Cyclases↗

PubMed1994

[A case of jejunal leiomyoma in the unknown site of bleeding findings by scintigraphy with 99mTc red blood cells].

Explore the source record for details and available documents.

Erythrocytes↗

PubMed1993

Continuous assessment of hemodynamic control by complex demodulation of cardiovascular variability.

Usefulness of complex demodulation (CDM) in assessing the frequency components of cardiovascular variability was assessed and, subsequently, this technique was utilized to determine the time-dependent responses of the low-frequency (LF) and high-frequency (HF) amplitudes of heart rate and blood pressure variabilities during postural tilt. CDM provides the time-dependent changes in amplitude of a particular frequency component on a continuous basis. Analysis of simulated data showed that CDM has sufficient frequency resolution to separately measure LF and HF amplitudes with a time resolution < 15 s and that CDM is robust to alterations in the frequency of the components. Analysis of actual data during postural tilt test in 23 young healthy subjects demonstrated that the HF amplitude of heart rate, an index of cardiac parasympathetic tone, rapidly decayed with head-up tilt (P < 0.01) and increased quickly showing an overshoot with tilt back to the supine position (P < 0.01). The LF amplitude of blood pressure, an index of vasomotor sympathetic activity, showed marked rhythmic fluctuation at an interval of 48-100 s during head-up tilt (P < 0.01), synchronizing with similar fluctuation in the LF amplitude of heart rate (P < 0.01). These results suggest that CDM can be used to provide a continuous assessment of cardiovascular variability components and that the dynamic responses of autonomic circulatory control to upright posture result in a phasic modulation of LF amplitude.

Adult↗

PubMed1993

[Structure of adenylate cyclase and the coupling with the receptor-G protein system].

Adenylate cyclase is a key enzyme that couples with both the stimulatory and inhibitory G proteins (Gs and Gi). The cyclase has been purified and shown to be a glycoprotein of molecular weight 115,000-180,000. Cloning of cDNAs for adenylate cyclase showed that the cyclase is a member of a large family consisting of a variety of subtypes of the enzyme. These subtypes show different responses to calmodulin and G protein beta gamma subunits, and their distributions in tissues and organs are also different. This suggests that each subtype is involved in a particular physiological function. The general structure of adenylate cyclase is composed of two cytoplasmic domains and two membrane-spanning domains, each of which contains 6 transmembrane spans (12 spans in a molecule). The amino acid sequence of each cytoplasmic domain, which is thought to contain a nucleotide (ATP) binding site, is well-conserved among the various subtypes. This review also focuses on the regulation of adenylate cyclase activity by G protein subunits, particularly on several models for adenylate cyclase inhibition by Gi. As one of these mechanisms, direct inhibition of adenylate cyclase by the beta gamma subunits recently demonstrated by us will be discussed.

Adenylyl Cyclases↗

PubMed1993

G protein beta gamma-subunits inhibit purified adenylate cyclase independent of the activation by Ca2+ and calmodulin.

Adenylate cyclase purified by affinity chromatography was activated about 2.5-fold in a Ca(2+)- and calmodulin-dependent fashion. G protein beta gamma-subunits, an inhibitor in the receptor-mediated inhibition of adenylate cyclase, inhibited the purified cyclase by more than 80%. The extent of beta gamma-induced inhibition was not affected by the activation with Ca2+ and calmodulin. Moreover, the prior addition of the beta gamma-subunits to the cyclase did not prevent the subsequent activation of the enzyme by Ca2+ and calmodulin. We conclude that the beta gamma-subunits inhibit adenylate cyclase activity in a calmodulin-independent mode.

Adenylyl Cyclase Inhibitors↗

PubMed1991

Single administration of captopril and combined use with beta-blocker and/or thiazide diuretic in the treatment of essential hypertension.

Thirty-four patients with essential hypertension at WHO stage I or II were divided into three groups. Group I consisted of 22 cases who displayed normal renin activity (NR) or low renin activity (LR) and who received a single administration of captopril. Group II consisted of 6 cases given beta-blockers after administration of captopril. Group III consisted of 6 cases in whom beta-blocker was replaced with thiazide diuretics after administration of captopril alone. Blood pressure decreased significantly by captopril treatment alone in group I of the NR and LR subgroups (except for the diastolic blood pressure [DBP] of the NR subgroup) and fell below the target blood pressure (SBP of 165 mmHg and DBP of 95 mmHg) in 86% of the NR subgroup and 73% of the LR subgroup. Combined treatment with captopril and beta-blocker in Group II did not decrease blood pressure any lower than with captopril alone treatment and achieved the target blood pressure in only 50% of the patients. In group III, combined treatment with captopril and thiazide achieved the target blood pressure in 100% of the patients. Plasma renin activity (PRA) was increased by captopril but reduced by captopril in combination with beta-blocker. However, when beta-blocker was replaced with thiazide, PRA increased. The serum sodium concentration was significantly reduced in the LR subgroup after a single administration of captopril, but there was no other variation.

Acebutolol↗