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Hydrogen-bonding dynamics between adjacent blades in G-protein beta-subunit regulates GIRK channel activation.

ABSTRACT: Functionally critical domains in the betagamma-subunits of the G-protein (Gbetagamma) do not undergo large structural rearrangements upon binding to other proteins. Here we show that a region containing Ser(67) and Asp(323) of Gbetagamma is a critical determinant of G-protein-gated inwardly rectifying K(+) (GIRK) channel activation and undergoes only small structural changes upon mutation of these residues. Using an interactive experimental and computational approach, we show that mutants that form a hydrogen-bond between positions 67 and 323 do not activate a GIRK channel. We also show that in the absence of hydrogen-bonding between these positions, other factors, such as the displacement of the crucial Ggamma residues Pro(60) and Phe(61), can impair Gbetagamma-mediated GIRK channel activation. Our results imply that the dynamic nature of the hydrogen-bonding pattern in the wild-type serves an important functional role that regulates GIRK channel activation by Gbetagamma and that subtle changes in the flexibility of critical domains could have substantial functional consequences. Our results further strengthen the notion that the dynamic regulation of multiple interactions between Gbetagamma and effectors provides for a complex regulatory process in cellular functions.

SUBMITTER: Mirshahi T

PROVIDER: S-EPMC1414569 | biostudies-literature | 2006 Apr

REPOSITORIES: biostudies-literature

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Hydrogen-bonding dynamics between adjacent blades in G-protein beta-subunit regulates GIRK channel activation.

Mirshahi Tooraj T Logothetis Diomedes E DE Rosenhouse-Dantsker Avia A

Biophysical journal 20060120 8

Functionally critical domains in the betagamma-subunits of the G-protein (Gbetagamma) do not undergo large structural rearrangements upon binding to other proteins. Here we show that a region containing Ser(67) and Asp(323) of Gbetagamma is a critical determinant of G-protein-gated inwardly rectifying K(+) (GIRK) channel activation and undergoes only small structural changes upon mutation of these residues. Using an interactive experimental and computational approach, we show that mutants that f ...[more]

PMID: 16428273

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Project description:During early stages of Alzheimer's disease (AD), synaptic dysfunction induced by toxic amyloid-β (Aβ) is present before the accumulation of histopathological hallmarks of the disease. This scenario produces impaired functioning of neuronal networks, altered patterns of synchronous activity and severe functional deficits mainly due to hyperexcitability of hippocampal networks. The molecular mechanisms underlying these alterations remain unclear but functional evidence, shown by our laboratory and others, points to the involvement of receptors/channels which modulate neuronal excitability, playing a pivotal role in early Aβ-induced AD pathogenesis. In particular, two potassium channels that control neuronal excitability, G protein-coupled activated inwardly-rectifying potassium channel (GirK), and voltage-gated K channel (KCNQ), have been recently linked to Aβ pathophysiology in the hippocampus. Specifically, by using Aβ25-35, we previously found that GirK conductance is greatly decreased in the hippocampus, and similar effects have also been reported on KCNQ conductance. Thus, in the present study, our goal was to determine the effect of Aβ on the transcriptional expression pattern of 17 genes encoding neurotransmitter receptors and associated channels which maintain excitatory-inhibitory neurotransmission balance in hippocampal circuits, with special focus in potassium channels. For this purpose, we designed a systematic and reliable procedure to analyze mRNA expression by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) in hippocampal rat slices incubated with Aβ25-35. We found that: 1) Aβ down-regulated mRNA expression of ionotropic GluN1 and metabotropic mGlu1 glutamate receptor subunits as previously reported in other AD models; 2) Aβ also reduced gene expression levels of GirK2, 3, and 4 subunits, and KCNQ2 and 3 subunits, but did not change expression levels of its associated GABAB and M1 receptors, respectively. Our results provide evidence that Aβ can modulate the expression of these channels which could affect the hippocampal activity balance underlying learning and memory processes impaired in AD.

Dataset Information

Hydrogen-bonding dynamics between adjacent blades in G-protein beta-subunit regulates GIRK channel activation.

Publications

Hydrogen-bonding dynamics between adjacent blades in G-protein beta-subunit regulates GIRK channel activation.

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