Altered myocardial Gs protein and adenylyl cyclase signaling in rats exposed to chronic hypoxia and normoxic recovery

2003 ◽  
Vol 94 (6) ◽  
pp. 2423-2432 ◽  
Author(s):  
Markéta Hrbasová ◽  
Jiri Novotny ◽  
Lucie Hejnová ◽  
František Kolář ◽  
Jan Neckář ◽  
...  
Keyword(s):  
Adenylyl Cyclase ◽  
G Protein ◽  
Contractile Function ◽  
Left Ventricular ◽  
Adaptation To Hypoxia ◽  
Adrenergic Stimulation ◽  
Α Subunit ◽  
Stimulatory G Protein ◽  
Membrane Bound ◽  
The Right

The present work has analyzed the consequences of chronic intermittent high-altitude hypoxia for functioning of the G protein-mediated adenylyl cyclase (AC) signaling system in the right (RV) and left ventricular (LV) myocardium in rats. Adaptation to hypoxia did not appreciably affect the number of β-adrenoceptors and the content of predominantly membrane-bound α-subunit (Gsα) of the stimulatory G protein, but it raised the amount of cytosolic Gsα in RV. The levels of myocardial inhibitory Gα protein were not altered. Activity of AC stimulated by GTP, fluoride, forskolin, or isoprotertenol was reduced by ∼50% in RV from chronically hypoxic rats, and a weaker depression was also found in LV. In addition, hypoxia significantly diminished a functional activity of membrane-bound Gsα in both RV and LV. The RV baseline contractile function was markedly increased in chronically hypoxic animals, and its sensitivity to β-adrenergic stimulation was decreased. Animals recovering from hypoxia for 5 wk still exhibited markedly elevated levels of cytosolic Gsα and significantly lower activity of AC in RV than did age-matched controls, but contractile responsiveness to β-agonists was normal.

scholarly journals Receptor-Mediated Adenylyl Cyclase Activation Through XLαs, the Extra-Large Variant of the Stimulatory G Protein α-Subunit

2002 ◽  
Vol 16 (8) ◽  
pp. 1912-1919 ◽  
Author(s):  
Murat Bastepe ◽  
Yasemin Gunes ◽  
Beatriz Perez-Villamil ◽  
Joy Hunzelman ◽  
Lee S. Weinstein ◽  
...  
Keyword(s):  
Adenylyl Cyclase ◽  
G Protein ◽  
Adrenergic Receptor ◽  
Α Subunit ◽  
Exon 2 ◽  
Amino Terminal ◽  
Stimulatory G Protein ◽  
Β2 Adrenergic Receptor ◽  
Carboxyl Terminal ◽  
G Protein Α Subunit

Abstract XLαs, the large variant of the stimulatory G protein α subunit (Gsα), is derived from GNAS1 through the use of an alternative first exon and promoter. Gsα and XLαs have distinct amino-terminal domains, but are identical over the carboxyl-terminal portion encoded by exons 2–13. XLαs can mimic some functions of Gsα, including βγ interaction and adenylyl cyclase stimulation. However, previous attempts to demonstrate coupling of XLαs to typically Gs-coupled receptors have not been successful. We now report the generation of murine cell lines that carry homozygous disruption of Gnas exon 2, and are therefore null for endogenous XLαs and Gsα (GnasE2−/E2−). GnasE2−/E2− cells transfected with plasmids encoding XLαs and different heptahelical receptors, including the β2-adrenergic receptor and receptors for PTH, TSH, and CRF, showed agonist-mediated cAMP accumulation that was indistinguishable from that observed with cells transiently coexpressing Gsα and these receptors. Our findings thus indicate that XLαs is capable of functionally coupling to receptors that normally act via Gsα.

scholarly journals Adenylyl cyclases (ACs) (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

2019 ◽  
Vol 2019 (4) ◽  
Author(s):  
Carmen W. Dessauer ◽  
Rennolds Ostrom ◽  
Roland Seifert ◽  
Val J. Watts
Keyword(s):  
Cyclic Amp ◽  
Adenylyl Cyclase ◽  
G Protein ◽  
Adenylyl Cyclases ◽  
Adenylyl Cyclase Activity ◽  
Α Subunit ◽  
Soluble Adenylyl Cyclase ◽  
Catalytic Domains ◽  
Stimulatory G Protein ◽  
Membrane Spanning

Adenylyl cyclase, E.C. 4.6.1.1, converts ATP to cyclic AMP and pyrophosphate. Mammalian membrane-delimited adenylyl cyclases (nomenclature as approved by the NC-IUPHAR Subcommittee on Adenylyl cyclases [9]) are typically made up of two clusters of six TM domains separating two intracellular, overlapping catalytic domains that are the target for the nonselective activators Gαs (the stimulatory G protein α subunit) and forskolin (except AC9, [21]). adenosine and its derivatives (e.g. 2',5'-dideoxyadenosine), acting through the P-site,are inhibitors of adenylyl cyclase activity [27]. Four families of membranous adenylyl cyclase are distinguishable: calmodulin-stimulated (AC1, AC3 and AC8), Ca2+- and Gβγ-inhibitable (AC5, AC6 and AC9), Gβγ-stimulated and Ca2+-insensitive (AC2, AC4 and AC7), and forskolin-insensitive (AC9) forms. A soluble adenylyl cyclase (AC10) lacks membrane spanning regions and is insensitive to G proteins.It functions as a cytoplasmic bicarbonate (pH-insensitive) sensor [5].

scholarly journals Repression of Adipogenesis by Adenylyl Cyclase Stimulatory G-protein α Subunit Is Expressed within Region 146-220

1996 ◽  
Vol 271 (36) ◽  
pp. 22022-22029 ◽  
Author(s):  
Hsien-yu Wang ◽  
Gary L. Johnson ◽  
Xunxian Liu ◽  
Craig C. Malbon
Keyword(s):  
Adenylyl Cyclase ◽  
G Protein ◽  
Α Subunit ◽  
Stimulatory G Protein ◽  
G Protein Α Subunit

Viscerosomatic interaction induced by myocardial ischemia in conscious dogs

2007 ◽  
Vol 103 (2) ◽  
pp. 511-517 ◽  
Author(s):  
Patricia A. Gwirtz ◽  
Jerry Dickey ◽  
David Vick ◽  
Maurice A. Williams ◽  
Brian Foresman
Keyword(s):  
Myocardial Ischemia ◽  
Contractile Function ◽  
Muscle Tone ◽  
Muscle Tension ◽  
Left Ventricular ◽  
Diagnostic Potential ◽  
Myocardial Contractile ◽  
Muscle Groups ◽  
The Right ◽  
Somatic Response

Studies tested the hypothesis that myocardial ischemia induces increased paraspinal muscular tone localized to the T2–T5 region that can be detected by palpatory means. This is consistent with theories of manual medicine suggesting that disturbances in visceral organ physiology can cause increases in skeletal muscle tone in specific muscle groups. Clinical studies in manual and traditional medicine suggest this phenomenon occurs during episodes of myocardial ischemia and may have diagnostic potential. However, there is little direct evidence of a cardiac-somatic mechanism to explain these findings. Chronically instrumented dogs [12 neurally intact and 3 following selective left ventricular (LV) sympathectomy] were examined before, during, and after myocardial ischemia. Circumflex blood flow (CBF), left ventricular contractile function, electromyographic (EMG) analysis, and blinded manual palpatory assessments (MPA) of tissue over the transverse spinal processes at segments T2–T5 and T11–T12 (control) were performed. Myocardial ischemia was associated with a decrease in myocardial contractile function and an increase in heart rate. MPA revealed increases in muscle tension and texture/firmness during ischemia in the T2–T5 segments on the left, but not on the right or in control segments. EMG demonstrated increased amplitude for the T4–T5 segments. After LV sympathectomy, MPA and EMG evidence of increased muscle tone were absent. In conclusion, myocardial ischemia is associated with significant increased paraspinal muscle tone localized to the left side T4–T5 myotomes in neurally intact dogs. LV sympathectomy eliminates the somatic response, suggesting that sympathetic neural traffic between the heart and somatic musculature may function as the mechanism for the interaction.

Inotropic sensitivity to beta-adrenergic stimulation in early sepsis

1988 ◽  
Vol 255 (4) ◽  
pp. H699-H703 ◽  
Author(s):  
L. W. Smith ◽  
K. H. McDonough
Keyword(s):  
Contractile Function ◽  
Plasma Catecholamines ◽  
Left Ventricular ◽  
Adrenergic Stimulation ◽  
Maximal Increase ◽  
Beta Adrenergic ◽  
Arterial Blood ◽  
Myocardial Contractile ◽  
Early Sepsis

In early sepsis, maintenance of in vivo cardiovascular performance is at least partly dependent on sympathetic support to hearts with intrinsic contractile defects. Yet prolonged sympathetic stimulation, as occurs in sepsis, would be expected to alter the heart's ability to respond to this stimulation. We have investigated myocardial inotropic sensitivity to beta-adrenergic stimulation in a model of sepsis in which animals, at the time studied, exhibited bacteremia, normal arterial blood pressure and cardiac output, elevated heart rate, and elevated plasma catecholamines. Intrinsic myocardial contractile function, as assessed by the maximal rate of left ventricular pressure development (LV dP/dtmax) in an isovolumically contracting heart preparation, was significantly depressed in septic animals. To determine whether hearts from septic animals could respond normally to beta-adrenergic stimulation, we studied inotropic response to a bolus of isoproterenol in these isolated hearts. With maximal isoproterenol stimulation, hearts from septic animals were able to attain the same dP/dtmax as were hearts from control animals. With lower levels of isoproterenol, there was also no difference in inotropic indexes between the two groups when response was expressed as a percent of the maximal increase in dP/dtmax achieved with isoproterenol. These results suggest that in early sepsis, despite intrinsic myocardial contractile dysfunction, the ability of the heart to modulate its inotropic state in response in beta-adrenergic stimulation is intact.

scholarly journals Heterologous Facilitation of G Protein-Activated K+ Channels by β-Adrenergic Stimulation via Camp-Dependent Protein Kinase

2000 ◽  
Vol 115 (5) ◽  
pp. 547-558 ◽  
Author(s):  
Carmen Müllner ◽  
Dimitry Vorobiov ◽  
Amal Kanti Bera ◽  
Yasuhito Uezono ◽  
Daniel Yakubovich ◽  
...  
Keyword(s):  
G Protein ◽  
Slow Component ◽  
Xenopus Laevis Oocytes ◽  
Adrenergic Stimulation ◽  
Current Increase ◽  
Girk Channels ◽  
Α Subunit ◽  
K Channels ◽  
Adult Rat ◽  
Whole Cell Patch Clamp

To investigate possible effects of adrenergic stimulation on G protein–activated inwardly rectifying K+ channels (GIRK), acetylcholine (ACh)-evoked K+ current, IKACh, was recorded from adult rat atrial cardiomyocytes using the whole cell patch clamp method and a fast perfusion system. The rise time of IKACh was 0.4 ± 0.1 s. When isoproterenol (Iso) was applied simultaneously with ACh, an additional slow component (11.4 ± 3.0 s) appeared, and the amplitude of the elicited IKACh was increased by 22.9 ± 5.4%. Both the slow component of activation and the current increase caused by Iso were abolished by preincubation in 50 μM H89 {N-[2-((p -bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamide, a potent inhibitor of PKA}. This heterologous facilitation of GIRK current by β-adrenergic stimulation was further studied in Xenopus laevis oocytes coexpressing β2-adrenergic receptors, m2 -receptors, and GIRK1/GIRK4 subunits. Both Iso and ACh elicited GIRK currents in these oocytes. Furthermore, Iso facilitated ACh currents in a way, similar to atrial cells. Cytosolic injection of 30–60 pmol cAMP, but not of Rp-cAMPS (a cAMP analogue that is inhibitory to PKA) mimicked the β2-adrenergic effect. The possibility that the potentiation of GIRK currents was a result of the phosphorylation of the β-adrenergic receptor (β2AR) by PKA was excluded by using a mutant β2AR in which the residues for PKA-mediated modulation were mutated. Overexpression of the α subunit of G proteins (Gαs) led to an increase in basal as well as agonist-induced GIRK1/GIRK4 currents (inhibited by H89). At higher levels of expressed Gαs, GIRK currents were inhibited, presumably due to sequestration of the β/γ subunit dimer of G protein. GIRK1/GIRK5, GIRK1/GIRK2, and homomeric GIRK2 channels were also regulated by cAMP injections. Mutant GIRK1/GIRK4 channels in which the 40 COOH-terminal amino acids (which contain a strong PKA phosphorylation consensus site) were deleted were also modulated by cAMP injections. Hence, the structural determinant responsible is not located within this region. We conclude that, both in atrial myocytes and in Xenopus oocytes, β-adrenergic stimulation potentiates the ACh-evoked GIRK channels via a pathway that involves PKA-catalyzed phosphorylation downstream from β2AR.

Left ventricular function during lethal and sublethal endotoxemia in swine

1986 ◽  
Vol 251 (2) ◽  
pp. H364-H373 ◽  
Author(s):  
R. D. Goldfarb ◽  
L. M. Nightingale ◽  
P. Kish ◽  
P. B. Weber ◽  
D. J. Loegering
Keyword(s):  
Low Dose ◽  
Diastolic Pressure ◽  
Contractile Function ◽  
Lethal Dose ◽  
Cardiac Contractility ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
High Dose ◽  
Adrenergic Stimulation ◽  
And Function

Our previous studies suggested that after a median lethal dose (LD50) of endotoxin, cardiac contractility was depressed in nonsurviving dogs. The canine cardiovascular system is unlike humans in that dogs have a hepatic vein sphincter that is susceptible to adrenergic stimulation capable of raising hepatic and splanchnic venous pressures. We retested the hypothesis that lethality after endotoxin administration is associated with cardiac contractile depression in pigs, because the hepatic circulation in this species is similar to that of humans. We compared cardiac mechanical function of pigs administered a high dose (250 micrograms/kg) or a low dose (100 micrograms/kg) endotoxin by use of the slope of the end-systolic pressure-diameter relationship (ESPDR) as well as other measurements of cardiac performance. In all the pigs administered a high dose, ESPDR demonstrated a marked, time-dependent depression, whereas we observed no significant ESPDR changes after low endotoxin doses. The other cardiodynamic variables were uninterpretable, due to the significant changes in heart rate, end-diastolic diameter (preload), and aortic diastolic pressure (afterload). Plasma myocardial depressant factor activity accumulated in all endotoxin-administered animals, tending to be greater in the high-dose group. In this group, both subendocardial blood flow and global function were depressed, whereas pigs administered the low dose of endotoxin demonstrated slight, but nonsignificant, increases in flow and function. These observations indicate that myocardial contractile depression is associated with a lethal outcome to high doses of endotoxin. One possible mechanism for this loss of contractile function may be a relative hypoperfusion of the subendocardium.

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