Erratum to: Multiple Pharmacological Actions of Centrally Acting Antitussives ^|^mdash; Do They Target G Protein-Coupled Inwardly Rectifying K+ (GIRK) Channels? [Journal of Pharmacological Sciences Vol. 120 (2012) No. 3 p. 146-151]

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

Anesthesiology ◽

10.1097/00000542-200107000-00025 ◽

2001 ◽

Vol 95 (1) ◽

pp. 144-153 ◽

Cited By ~ 45

Author(s):

Tomohiro Yamakura ◽

Joanne M. Lewohl ◽

R. Adron Harris

Keyword(s):

Nitrous Oxide ◽

Potassium Channels ◽

G Protein ◽

Volatile Anesthetics ◽

General Anesthetics ◽

Girk Channels ◽

Intravenous Anesthetics ◽

Amino Acid Mutations ◽

Inwardly Rectifying ◽

G Protein Coupled

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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Multiple Pharmacological Actions of Centrally Acting Antitussives ^|^mdash; Do They Target G Protein-Coupled Inwardly Rectifying K+ (GIRK) Channels?

Journal of Pharmacological Sciences ◽

10.1254/jphs.12r07cp ◽

2012 ◽

Vol 120 (3) ◽

pp. 146-151 ◽

Cited By ~ 6

Author(s):

Kazuo Takahama

Keyword(s):

G Protein ◽

Girk Channels ◽

Inwardly Rectifying ◽

G Protein Coupled

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Sign Inversion in Photopharmacology: Incorporation of Cyclic Azobenzenes in Photoswitchable Potassium Channel Blockers and Openers

10.26434/chemrxiv.8014580 ◽

2019 ◽

Author(s):

Julie Trads ◽

Katharina Hüll ◽

Bryan Matsuura ◽

Laura Laprell ◽

Timm Fehrentz ◽

...

Keyword(s):

G Protein ◽

Biologically Active ◽

Channel Blockers ◽

Biological Applications ◽

Girk Channels ◽

Voltage Gated ◽

Sign Inversion ◽

Potassium Channel Blockers ◽

Inwardly Rectifying ◽

G Protein Coupled

Photopharmacology relies on ligands that change their pharmacodynamics upon photoisomerization. Many of these ligands are azobenzenes that are thermodynamically more stable in their elongated transconfiguration, which predominates in the dark. Often, they are biologically active in this form and lose activity upon irradiation and photoisomerization to their cis-isomer. Recently, cyclic azobenzenes, so-called diazocines, have emerged. They are thermodynamically more stable in their bent cis‑form than in their elongated trans-form. Incorporation of these switches into a variety of photopharmaceuticals could convert dark-active ligands into dark-inactive ligands, which is preferred in most biological applications. This “pharmacological sign-inversion” is demonstrated for a photochromic blocker of voltage-gated potassium channels, termed CAL, and a photochromic opener of G-protein-coupled inwardly rectifying potassium (GIRK) channels, termed CLOGO.

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Regulators of G-Protein Signaling (RGS) Proteins Promote Receptor Coupling to G-Protein-Coupled Inwardly Rectifying Potassium (GIRK) Channels

Journal of Neuroscience ◽

10.1523/jneurosci.0516-18.2018 ◽

2018 ◽

Vol 38 (41) ◽

pp. 8737-8744 ◽

Cited By ~ 11

Author(s):

Kylie B. McPherson ◽

Emily R. Leff ◽

Ming-hua Li ◽

Claire Meurice ◽

Sherrica Tai ◽

...

Keyword(s):

G Protein ◽

G Protein Signaling ◽

Rgs Proteins ◽

Protein Signaling ◽

Girk Channels ◽

Receptor Coupling ◽

Inwardly Rectifying ◽

G Protein Coupled

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Sign Inversion in Photopharmacology: Incorporation of Cyclic Azobenzenes in Photoswitchable Potassium Channel Blockers and Openers

10.26434/chemrxiv.8014580.v1 ◽

2019 ◽

Author(s):

Julie Trads ◽

Katharina Hüll ◽

Bryan Matsuura ◽

Laura Laprell ◽

Timm Fehrentz ◽

...

Keyword(s):

G Protein ◽

Biologically Active ◽

Channel Blockers ◽

Biological Applications ◽

Girk Channels ◽

Voltage Gated ◽

Sign Inversion ◽

Potassium Channel Blockers ◽

Inwardly Rectifying ◽

G Protein Coupled

Photopharmacology relies on ligands that change their pharmacodynamics upon photoisomerization. Many of these ligands are azobenzenes that are thermodynamically more stable in their elongated transconfiguration, which predominates in the dark. Often, they are biologically active in this form and lose activity upon irradiation and photoisomerization to their cis-isomer. Recently, cyclic azobenzenes, so-called diazocines, have emerged. They are thermodynamically more stable in their bent cis‑form than in their elongated trans-form. Incorporation of these switches into a variety of photopharmaceuticals could convert dark-active ligands into dark-inactive ligands, which is preferred in most biological applications. This “pharmacological sign-inversion” is demonstrated for a photochromic blocker of voltage-gated potassium channels, termed CAL, and a photochromic opener of G-protein-coupled inwardly rectifying potassium (GIRK) channels, termed CLOGO.

Download Full-text