scholarly journals Structural basis of GIRK2 channel modulation by cholesterol and PIP2

2020 ◽  
Author(s):  
Yamuna Kalyani Mathiharan ◽  
Ian W. Glaaser ◽  
Yulin Zhao ◽  
Michael J. Robertson ◽  
Georgios Skiniotis ◽  
...  
Keyword(s):  
G Protein ◽  
Transmembrane Domain ◽  
Structural Data ◽  
Structural Basis ◽  
Girk Channels ◽  
Channel Modulation ◽  
Cryo Electron Microscopy ◽  
Cellular Excitability ◽  
Cholesteryl Hemisuccinate ◽  
Inwardly Rectifying

ABSTRACTG protein-gated inwardly rectifying potassium (GIRK) channels play important roles in controlling cellular excitability in the heart and brain. While structural data begin to unravel the molecular basis for G protein and alcohol dependent activation of GIRK channels, little is known about the modulation by cholesterol. Here, we present cryo-electron microscopy (cryoEM) structures of GIRK2 in the presence and absence of the cholesterol analog cholesteryl hemisuccinate (CHS), and PIP2. The structures and their comparison reveal that CHS binds near PIP2 in lipid-facing hydrophobic pockets of the transmembrane domain (TMD). CHS potentiates the effects of PIP2, which stabilizes the inter-domain region and promotes the engagement of the cytoplasmic domain (CTD) onto the transmembrane region. The results suggest that CHS acts as a positive allosteric modulator and identify novel therapeutic sites for modulating GIRK channels in the brain.

scholarly journals Structural basis for auxiliary subunit KCTD16 regulation of the GABABreceptor

2019 ◽  
Vol 116 (17) ◽  
pp. 8370-8379 ◽  
Author(s):  
Hao Zuo ◽  
Ian Glaaser ◽  
Yulin Zhao ◽  
Igor Kurinov ◽  
Lidia Mosyak ◽  
...  
Keyword(s):  
Structural Basis ◽  
Functional Coupling ◽  
Girk Channels ◽  
Receptor Complexes ◽  
Binding Interface ◽  
Tetramerization Domain ◽  
High Resolution Structure ◽  
Inwardly Rectifying ◽  
The Brain ◽  
Oligomerization Domain

Metabotropic GABABreceptors mediate a significant fraction of inhibitory neurotransmission in the brain. Native GABABreceptor complexes contain the principal subunits GABAB1and GABAB2, which form an obligate heterodimer, and auxiliary subunits, known as potassium channel tetramerization domain-containing proteins (KCTDs). KCTDs interact with GABABreceptors and modify the kinetics of GABABreceptor signaling. Little is known about the molecular mechanism governing the direct association and functional coupling of GABABreceptors with these auxiliary proteins. Here, we describe the high-resolution structure of the KCTD16 oligomerization domain in complex with part of the GABAB2receptor. A single GABAB2C-terminal peptide is bound to the interior of an open pentamer formed by the oligomerization domain of five KCTD16 subunits. Mutation of specific amino acids identified in the structure of the GABAB2–KCTD16 interface disrupted both the biochemical association and functional modulation of GABABreceptors and G protein-activated inwardly rectifying K+channel (GIRK) channels. These interfacial residues are conserved among KCTDs, suggesting a common mode of KCTD interaction with GABABreceptors. Defining the binding interface of GABABreceptor and KCTD reveals a potential regulatory site for modulating GABAB-receptor function in the brain.

scholarly journals Structural basis for the ethanol action on G-protein–activated inwardly rectifying potassium channel 1 revealed by NMR spectroscopy

2018 ◽  
Vol 115 (15) ◽  
pp. 3858-3863 ◽  
Author(s):  
Yuki Toyama ◽  
Hanaho Kano ◽  
Yoko Mase ◽  
Mariko Yokogawa ◽  
Masanori Osawa ◽  
...  
Keyword(s):  
Nervous System ◽  
Nmr Spectroscopy ◽  
Potassium Channel ◽  
G Protein ◽  
Structural Basis ◽  
Signaling Proteins ◽  
Inwardly Rectifying Potassium Channel ◽  
Wide Range ◽  
Inwardly Rectifying ◽  
Human Nervous System

Ethanol consumption leads to a wide range of pharmacological effects by acting on the signaling proteins in the human nervous system, such as ion channels. Despite its familiarity and biological importance, very little is known about the molecular mechanisms underlying the ethanol action, due to extremely weak binding affinity and the dynamic nature of the ethanol interaction. In this research, we focused on the primary in vivo target of ethanol, G-protein–activated inwardly rectifying potassium channel (GIRK), which is responsible for the ethanol-induced analgesia. By utilizing solution NMR spectroscopy, we characterized the changes in the structure and dynamics of GIRK induced by ethanol binding. We demonstrated here that ethanol binds to GIRK with an apparent dissociation constant of 1.0 M and that the actual physiological binding site of ethanol is located on the cavity formed between the neighboring cytoplasmic regions of the GIRK tetramer. From the methyl-based NMR relaxation analyses, we revealed that ethanol activates GIRK by shifting the conformational equilibrium processes, which are responsible for the gating of GIRK, to stabilize an open conformation of the cytoplasmic ion gate. We suggest that the dynamic molecular mechanism of the ethanol-induced activation of GIRK represents a general model of the ethanol action on signaling proteins in the human nervous system.

Involvement of G-protein-activated inwardly rectifying K+ (GIRK) channels in opioid-induced analgesia

2000 ◽  
Vol 38 (1) ◽  
pp. 113-116 ◽  
Author(s):  
Kazutaka Ikeda ◽  
Toru Kobayashi ◽  
Toshiro Kumanishi ◽  
Hiroaki Niki ◽  
Ryoji Yano
Keyword(s):  
G Protein ◽  
Girk Channels ◽  
Inwardly Rectifying

scholarly journals Activation of G-protein-gated inwardly rectifying potassium (Kir3/GirK) channels rescues hippocampal functions in a mouse model of early amyloid-β pathology

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Irene Sánchez-Rodríguez ◽  
Sara Temprano-Carazo ◽  
Alberto Nájera ◽  
Souhail Djebari ◽  
Javier Yajeya ◽  
...  
Keyword(s):  
Mouse Model ◽  
G Protein ◽  
Amyloid Β ◽  
Girk Channels ◽  
Inwardly Rectifying

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

2014 ◽  
Vol 592 (22) ◽  
pp. 5079-5092 ◽  
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

Rapid desensitization of G protein-gated inwardly rectifying K+ currents is determined by G protein cycle

2004 ◽  
Vol 287 (1) ◽  
pp. C182-C191 ◽  
Author(s):  
Joanne L. Leaney ◽  
Amy Benians ◽  
Sean Brown ◽  
Muriel Nobles ◽  
David Kelly ◽  
...  
Keyword(s):  
G Protein ◽  
Competitive Inhibition ◽  
Similar Degree ◽  
Channel Activation ◽  
Girk Channels ◽  
Membrane Hyperpolarization ◽  
Hek 293 ◽  
Fast Activation ◽  
Inwardly Rectifying ◽  
Stimulation Of

Activation of G protein-gated inwardly rectifying K+ (GIRK) channels, found in the brain, heart, and endocrine tissue, leads to membrane hyperpolarization that generates neuronal inhibitory postsynaptic potentials, slows the heart rate, and inhibits hormone release. During stimulation of Gi/o-coupled receptors and subsequent channel activation, it has been observed that the current desensitizes. In this study we examined mechanisms underlying fast desensitization of cloned heteromeric neuronal Kir3.1+3.2A and atrial Kir3.1+3.4 channels and also homomeric Kir3.0 currents in response to stimulation of several Gi/o G protein-coupled receptors (GPCRs) expressed in HEK-293 cells (adenosine A1, adrenergic α2A, dopamine D2S, M4 muscarinic, and GABAB1b/2 receptors). We found that all agonist-induced currents displayed a similar degree of desensitization except the adenosine A1 receptor, which exhibits an additional desensitizing component. Using the nonhydrolyzable GTP analog guanosine 5′- O-(3-thiotriphosphate) (GTPγS), we found that this is due to a receptor-dependent, G protein-independent process. Using Ca2+ imaging we showed that desensitization is unlikely to be accounted for solely by phospholipase C activation and phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis. We examined the contribution of the G protein cycle and found the following. First, agonist concentration is strongly correlated with degree of desensitization. Second, competitive inhibition of GDP/GTP exchange by using nonhydrolyzable guanosine 5′- O-(2-thiodiphosphate) (GDPβS) has two effects, a slowing of channel activation and an attenuation of the fast desensitization phenomenon. Finally, using specific Gα subunits we showed that ternary complexes with fast activation rates display more prominent desensitization than those with slower activation kinetics. Together our data suggest that fast desensitization of GIRK currents is accounted for by the fundamental properties of the G protein cycle.

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