Differential Effects of General Anesthetics on G Protein–coupled Inwardly Rectifying and Other Potassium Channels

Background General anesthetics differentially affect various families of potassium channels, and some potassium channels are suggested to be potential targets for anesthetics and alcohols. Methods The voltage-gated (ERG1, ELK1, and KCNQ2/3) and inwardly rectifying (GIRK1/2, GIRK1/4, GIRK2, IRK1, and ROMK1) potassium channels were expressed in Xenopus oocytes. Effects of volatile agents [halothane, isoflurane, enflurane, F3 (1-chloro-1,2,2-trifluorocyclobutane), and the structurally related nonimmobilizer F6 (1,2-dichlorohexafluorocyclobutane)], as well as intravenous (pentobarbital, propofol, etomidate, alphaxalone, ketamine), and gaseous (nitrous oxide) anesthetics and alcohols (ethanol and hexanol) on channel function were studied using a two-electrode voltage clamp. Results ERG1, ELK1, and KCNQ2/3 channels were either inhibited slightly or unaffected by concentrations corresponding to twice the minimum alveolar concentrations or twice the anesthetic EC50 of volatile and intravenous anesthetics and alcohols. In contrast, G protein-coupled inwardly rectifying potassium (GIRK) channels were inhibited by volatile anesthetics but not by intravenous anesthetics. The neuronal-type GIRK1/2 channels were inhibited by 2 minimum alveolar concentrations of halothane or F3 by 45 and 81%, respectively, whereas the cardiac-type GIRK1/4 channels were inhibited only by F3. Conversely, IRK1 and ROMK1 channels were completely resistant to all anesthetics tested. Current responses of GIRK2 channels activated by mu-opioid receptors were also inhibited by halothane. Nitrous oxide (approximately 0.6 atmosphere) slightly but selectively potentiated GIRK channels. Results of chimeric and multiple amino acid mutations suggest that the region containing the transmembrane domains, but not the pore-forming domain, may be involved in determining differences in anesthetic sensitivity between GIRK and IRK channels. Conclusions G protein-coupled inwardly rectifying potassium channels, especially those composed of GIRK2 subunits, were inhibited by clinical concentrations of volatile anesthetics. This action may be related to some side effects of these agents.

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Endocannabinoids Modulate N-Type Calcium Channels and G-Protein-Coupled Inwardly Rectifying Potassium Channels via CB1 Cannabinoid Receptors Heterologously Expressed in Mammalian Neurons

Molecular Pharmacology ◽

10.1124/mol.65.3.665 ◽

2004 ◽

Vol 65 (3) ◽

pp. 665-674 ◽

Cited By ~ 91

Author(s):

Juan Guo ◽

Stephen R. Ikeda

Keyword(s):

Potassium Channels ◽

Calcium Channels ◽

G Protein ◽

Cannabinoid Receptors ◽

Inwardly Rectifying Potassium Channels ◽

Inwardly Rectifying ◽

G Protein Coupled

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Suprachiasmatic nucleus function and circadian entrainment are modulated by G protein‐coupled inwardly rectifying (GIRK) channels

The Journal of Physiology ◽

10.1113/jphysiol.2014.282079 ◽

2014 ◽

Vol 592 (22) ◽

pp. 5079-5092 ◽

Cited By ~ 7

Author(s):

L. M. Hablitz ◽

H. E. Molzof ◽

J. R. Paul ◽

R. L. Johnson ◽

K. L. Gamble

Keyword(s):

G Protein ◽

Suprachiasmatic Nucleus ◽

Girk Channels ◽

Inwardly Rectifying ◽

G Protein Coupled

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Dopamine inhibits GABAA currents in ventral tegmental area dopamine neurons via activation of presynaptic G-protein coupled inwardly-rectifying potassium channels

Neuroscience ◽

10.1016/j.neuroscience.2009.11.045 ◽

2010 ◽

Vol 165 (4) ◽

pp. 1159-1169 ◽

Cited By ~ 35

Author(s):

A. Michaeli ◽

R. Yaka

Keyword(s):

Potassium Channels ◽

Ventral Tegmental Area ◽

G Protein ◽

Dopamine Neurons ◽

Inwardly Rectifying Potassium Channels ◽

Ventral Tegmental ◽

Inwardly Rectifying ◽

G Protein Coupled

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Human Adrenal Glomerulosa Cells Express K2P and GIRK Potassium Channels that are inhibited by AngII and ACTH

AJP Cell Physiology ◽

10.1152/ajpcell.00118.2021 ◽

2021 ◽

Author(s):

John J. Enyeart ◽

Judith A. Enyeart

Keyword(s):

G Protein ◽

Zona Glomerulosa ◽

Time Dependent ◽

Aldosterone Secretion ◽

Girk Channels ◽

Whole Cell ◽

Whole Cell Patch Clamp ◽

Girk Channel ◽

Inwardly Rectifying ◽

G Protein Coupled

In whole-cell patch clamp recordings, it was discovered that normal human adrenal zona glomerulosa (AZG) cells express members of the three major families of K+ channels. Among these are a two pore (K2P) leak-type and a G-protein-coupled, inwardly-rectifying (GIRK) channel, both inhibited by peptide hormones that stimulate aldosterone secretion. The K2P current displayed properties identifying it as TREK-1 (KCNK2). This outwardly-rectifying current was activated by arachidonic acid and inhibited by angiotensin II (AngII), adrenocorticotrophic hormone (ACTH), and forskolin. The activation and inhibition of TREK-1 was coupled to AZG cell hyperpolarization and depolarization, respectively. A second K2P channel, TASK-1 (KCNK3), was expressed at a lower density in AZG cells. Human AZG cells also express inwardly rectifying K+ current(s) (KIR) that include quasi-instantaneous and time-dependent components. This is the first report demonstrating the presence of KIR in whole cell recordings from AZG cells of any species. The time-dependent current was selectively inhibited by AngII, and ACTH, identifying it as a G protein-coupled (GIRK) channel, most likely KIR3.4 (KCNJ5). The quasi-instantaneous KIR current was not inhibited by AngII or ACTH, and may be a separate non-GIRK current. Finally, AZG cells express a voltage-gated, rapidly inactivating K+ current whose properties identified as KV1.4 (KCNA4), a conclusion confirmed by Northern blot. These findings demonstrate that human AZG cells express K2P and GIRK channels whose inhibition by AngII and ACTH are likely coupled to depolarization-dependent secretion. They further demonstrate that human AZG K+ channels differ fundamentally from the widely adopted rodent models for human aldosterone secretion.

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Galanin Activates G Protein Gated Inwardly Rectifying Potassium Channels and Suppresses Kisspeptin-10 Activation of GnRH Neurons

Endocrinology ◽

10.1210/en.2016-1064 ◽

2016 ◽

Vol 157 (8) ◽

pp. 3197-3212 ◽

Cited By ~ 6

Author(s):

Stephanie Constantin ◽

Susan Wray

Keyword(s):

Potassium Channels ◽

G Protein ◽

Detection Threshold ◽

Calcium Oscillations ◽

Inwardly Rectifying Potassium Channels ◽

Gnrh Neurons ◽

Series Of Experiments ◽

Galanin Receptors ◽

Inwardly Rectifying ◽

G Protein Coupled

GnRH neurons are regulated by hypothalamic kisspeptin neurons. Recently, galanin was identified in a subpopulation of kisspeptin neurons. Although the literature thoroughly describes kisspeptin activation of GnRH neurons, little is known about the effects of galanin on GnRH neurons. This study investigated whether galanin could alter kisspeptin signaling to GnRH neurons. GnRH cells maintained in explants, known to display spontaneous calcium oscillations, and a long-lasting calcium response to kisspeptin-10 (kp-10), were used. First, transcripts for galanin receptors (GalRs) were examined. Only GalR1 was found in GnRH neurons. A series of experiments was then performed to determine the action of galanin on kp-10 activated GnRH neurons. Applied after kp-10 activation, galanin 1–16 (Gal1–16) rapidly suppressed kp-10 activation. Applied with kp-10, Gal1–16 prevented kp-10 activation until its removal. To determine the mechanism by which galanin inhibited kp-10 activation of GnRH neurons, Gal1–16 and galanin were applied to spontaneously active GnRH neurons. Both inhibited GnRH neuronal activity, independent of GnRH neuronal inputs. This inhibition was mimicked by a GalR1 agonist but not by GalR2 or GalR2/3 agonists. Although Gal1–16 inhibition relied on Gi/o signaling, it was independent of cAMP levels but sensitive to blockers of G protein-coupled inwardly rectifying potassium channels. A newly developed bioassay for GnRH detection showed Gal1–16 decreased the kp-10-evoked GnRH secretion below detection threshold. Together, this study shows that galanin is a potent regulator of GnRH neurons, possibly acting as a physiological break to kisspeptin excitation.

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