Halothane attenuation of muscarinic inhibition of adenylate cyclase in rat heart

Narayanan, Tanjore K.; Confer, Rand; Dennison, Robert L.; Anthony, Betty L.; Aronstam, Robert S.

doi:10.1016/0006-2952(88)90774-5

Cited by 22 publications

(6 citation statements)

References 15 publications

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“…3) Activation of GIRK via dissociation of G ␤␥ from G ␣i would require G protein activation by halothane. This assumption is in clear contradiction to findings of other laboratories, which quite consistently showed the inhibition of G ␣i by halothane (Narayanan et al, 1988;Böhm et al, 1994;Pentyala et al, 1999). Hence, we conclude that activation of GIRK currents by halothane is a direct consequence of GIRK1/halothane interaction.…”

Section: Discussioncontrasting

confidence: 99%

“…In biochemical studies, halothane has been found to increase the basal activity of adenylyl cyclase of rat hearts by attenuation of the muscarinic inhibition (Narayanan et al, 1988). Further, it has been postulated that halothane prevents the dissociation of the G protein from the receptor (Aronstam et al, 1986) in rat brain or that halothane inhibits GDP-GTP exchange (Böhm et al, 1994, Pentyala et al, 1999.…”

Section: Discussionmentioning

confidence: 99%

“…This could reflect an interaction with either the muscarinic receptor, the G protein, or the channel protein itself. It has been reported that halothane disrupts receptor-G protein interactions (Dennison et al, 1987;Narayanan et al, 1988). Therefore, one could expect inhibition of acetylcholine-activated GIRK channels by halothane resulting from impaired G protein activation via the receptor.…”

Section: Halothane Effects On Girk Channels 285mentioning

confidence: 99%

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G Protein-Gated Inwardly Rectifying Potassium Channels Are Targets for Volatile Anesthetics

Weigl

Schultze-Seemann

2001

Mol Pharmacol

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G protein-gated inwardly rectifying potassium channels (GIRKs) are a family of homo-and hetero-oligomeric K ϩ channels composed of different subunits (GIRK1 to 4 in mammals). GIRK4 and GIRK1 are found mainly in the atrium, whereas neuronal cells predominantly express the GIRK1, GIRK2, and GIRK3 isoforms. When activated, GIRK channels slow the firing rate of atrial myocytes and neuronal cells. Because of their key role in controlling excitability, we investigated the influence of a prototypic anesthetic, halothane, on GIRK channels of different subunit composition expressed in Xenopus laevis oocytes. Halothane enhanced background currents through hetero-oligomeric GIRK1/GIRK4 and homo-oligomeric GIRK1 F137S channels but not through homo-oligomeric GIRK2 channels. This activation of basal current did not depend on the presence of coexpressed G protein-coupled receptors but instead required the presence of G ␤/␥ . In contrast to basal GIRK currents, the agonist-induced GIRK current (via coexpressed m 2 muscarinic receptors) was inhibited by halothane. For GIRK1/GIRK4 and GIRK1 F137S channels this inhibition was most pronounced at low concentrations of the anesthetic (0.1-0.3 mM) and occurred also when channels had been activated by guanosine-5Ј-O-(3-thio)triphosphate. This inhibition, however, was overridden by high concentrations of halothane (0.9 mM) and augmentation of the agonist-induced current was observed. This increase in agonist-induced current was never seen with GIRK2 homo-oligomeric channels. Agonist-induced currents mediated by GIRK2 channels were always inhibited by halothane with an IC 50 value of approximately 60 M. These data suggest a direct interaction of halothane with GIRK channels.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Halothane Effects On Girk Channels 285mentioning

confidence: 99%

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G Protein-Gated Inwardly Rectifying Potassium Channels Are Targets for Volatile Anesthetics

Weigl

Schultze-Seemann

2001

Mol Pharmacol

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“…From our previous experiments (14) we concluded that halothane was able to activate the GIRK1 channel, probably by increasing its affinity to G␤␥, and that the inhibition of agonist-activated GIRK channels was because of the impairment of the G protein signaling cascade. This is consistent with the findings of various other laboratories that demonstrate the inhibition of signaling through G␣ i by halothane (15)(16)(17)(18).…”

supporting

confidence: 93%

The Sensitivity of G Protein-activated K+ Channels toward Halothane Is Essentially Determined by the C Terminus

Milovic

Steinecker-Frohnwieser

Schultze-Seemann

et al. 2004

Journal of Biological Chemistry

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G protein-activated K(+) channels (GIRKs or Kir3.x) are targets for the volatile anesthetic, halothane. When coexpressed with the m(2) acetylcholine (ACh) receptor in Xenopus oocytes, agonist-activated GIRK1(F137S)- and GIRK2-mediated currents are inhibited by halothane, whereas in the absence of ACh, high concentrations of halothane induce GIRK1(F137S)-mediated currents. To elucidate the molecular mechanism of halothane action on GIRK currents of different subunit compositions, we constructed deletion mutants of GIRK1(F137S) (GIRK1(Delta363*)) and GIRK2 (GIRK2(Delta356)) lacking the C-terminal ends, as well as chimeric GIRK channels. Mutated GIRK channels showed normal currents when activated by ACh but exhibited different pharmacological properties toward halothane. GIRK2(Delta356) showed no sensitivity against the inhibitory action of halothane but was activated by halothane in the absence of an agonist. GIRK1(Delta363*) was activated by halothane more efficiently. Currents mediated by chimeric channels were inhibited by anesthetic concentrations that were at least 30-fold lower than those necessary to decrease GIRK2 wild type currents. Glutathione S-transferase pulldown experiments did not show displacement of bound Gbetagamma by halothane, indicating that halothane does not interfere with Gbetagamma binding. Single channel experiments revealed an influence of halothane on the gating of the channels: The agonist-induced currents of GIRK1 and GIRK2, carried mainly by brief openings, were inhibited, whereas higher concentrations of the anesthetic promoted long openings of GIRK1 channels. Because the C terminus is crucial for these effects, an interaction of halothane with the channel seems to be involved in the mechanism of current modulation.

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“…The present observations demonstrate that carbachol does not affect forskolin-or cAMP analog-induced increases in myocyte contractility, suggesting that muscarinic cholinergic agonist may not exert inhibitory effect at the level of adenylyl cyclase or cAMPdependent protein kinase, at least in adult rat single ventricular myocytes. Previous studies using several cardiac preparations, including adult rat whole heart, adult rat ventricle and guinea pig atria, have shown that carbachol (even at 10 Ìmol/l concentration) causes significant inhibition of forskolin-induced adenylyl cyclase activity [34][35][36]. However, under the conditions employed in the present study, carbachol (50 Ìmol/l) attenuates isoproterenol-induced cell shortening, but not forskolin-induced cell shortening.…”

Section: Discussioncontrasting

confidence: 60%

Pertussis Toxin-Sensitive G Protein but Not NO/cGMP Pathway Mediates the Negative Inotropic Effect of Carbachol in Adult Rat Cardiomyocytes

Sandirasegarane¹,

Diamond²

2003

Pharmacology

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Previous studies have shown that muscarinic inhibition of cardiac contractility is mediated by either activation of nitric oxide (NO)/guanosine 3′,5′-cyclic monophosphate (cGMP) pathway or stimulation of inhibitory G protein (G_i). However, it still remains controversial as to whether NO/cGMP pathway or G_i protein or both mediate(s) the negative inotropic effect of muscarinic agonists in adult ventricular myocytes. In the present study that involves the use of adult rat ventricular myocytes, the muscarinic agonist, carbachol, inhibited β-adrenergic (isoproterenol) stimulation of contractility (cell shortening) by 82% and increased cGMP levels by 49% within 6 min. Pretreatment of myocytes with soluble guanylyl cyclase inhibitor (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, ODQ) or NO synthase inhibitor (N^G-monomethyl-L-arginine, L-NMMA) for 30 min blocked carbachol-induced increases in cGMP levels. However, neither ODQ nor L-NMMA pretreatment had any effect on carbachol inhibition of isoproterenol-induced contractility. In addition, carbachol did not attenuate increases in myocyte contractility induced by forskolin (a direct activator of adenylyl cyclase) or 8-(4-chlorophenylthio)-adenosine 3′,5′-cyclic monophosphate (a cell-permeable cAMP analog which activates cAMP-dependent protein kinase). Pretreatment of myocytes with G_i protein inhibitor, pertussis toxin (PTX, 1 µg/ml), for 18–20 h abolished carbachol inhibition of isoproterenol-induced contractility. Furthermore, in ventricular myocytes isolated 3 days after in vivo treatment of rats with PTX (3 µg/100 g, i.p.), there was a complete loss of the negative inotropic effect of carbachol. These data indicate that pertussis toxin-sensitive G protein but not NO/cGMP pathway is required for muscarinic inhibition of β-adrenoceptor-mediated increases in contractility in adult rat ventricular myocytes.

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Halothane attenuation of muscarinic inhibition of adenylate cyclase in rat heart

Cited by 22 publications

References 15 publications

G Protein-Gated Inwardly Rectifying Potassium Channels Are Targets for Volatile Anesthetics

G Protein-Gated Inwardly Rectifying Potassium Channels Are Targets for Volatile Anesthetics

The Sensitivity of G Protein-activated K+ Channels toward Halothane Is Essentially Determined by the C Terminus

Pertussis Toxin-Sensitive G Protein but Not NO/cGMP Pathway Mediates the Negative Inotropic Effect of Carbachol in Adult Rat Cardiomyocytes

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