A Collision Coupling Model Governs the Activation of Neuronal GIRK1/2 Channels by Muscarinic-2 Receptors.

The G protein-activated Inwardly Rectifying K-channel (GIRK) modulates heart rate and neuronal excitability. Following G-Protein Coupled Receptor (GPCR)-mediated activation of heterotrimeric G proteins (Gαβγ), opening of the channel is obtained by direct binding of Gβγ subunits. Interestingly, GIRKs are solely activated by Gβγ subunits released from Gα-coupled GPCRs, despite the fact that all receptor types, for instance Gα-coupled, are also able to provide Gβγ subunits.

K 5.1-dependent CO /H -sensitive currents contribute to astrocyte heterogeneity across brain regions.

Astrocyte heterogeneity is an emerging concept in which astrocytes within or between brain regions show variable morphological and/or gene expression profiles that presumably reflect different functional roles. Recent evidence indicates that retrotrapezoid nucleus (RTN) astrocytes sense changes in tissue CO H to regulate respiratory activity; however, mechanism(s) by which they do so remain unclear. Alterations in inward K currents represent a potential mechanism by which CO /H signals may be conveyed to neurons.

Isoflurane inhibits a Kir4.1/5.1-like conductance in neonatal rat brainstem astrocytes and recombinant Kir4.1/5.1 channels in a heterologous expression system.

All inhalation anesthetics used clinically including isoflurane can suppress breathing; since this unwanted side effect can persist during the postoperative period and complicate patient recovery, there is a need to better understand how isoflurane affects cellular and molecular elements of respiratory control. Considering that astrocytes in a brainstem region known as the retrotrapezoid nucleus (RTN) contribute to the regulation of breathing in response to changes in CO/H (i.e.

DNA methylation: A mechanism for sustained alteration of KIR4.1 expression following central nervous system insult.

Kir4.1, a glial-specific inwardly rectifying potassium channel, is implicated in astrocytic maintenance of K homeostasis. Underscoring the role of Kir4.

Glial SIK3: A central player in ion and volume homeostasis in peripheral nerves.

The electrical properties of neuronal cells rely on gradients of ions across their membranes and the extracellular fluid (ECF) in which they are bathed. Little is known regarding how the ECF volume and content is maintained. In this issue, Li et al.

Glial Dysfunction in MeCP2 Deficiency Models: Implications for Rett Syndrome.

Rett syndrome (RTT) is a rare, X-linked neurodevelopmental disorder typically affecting females, resulting in a range of symptoms including autistic features, intellectual impairment, motor deterioration, and autonomic abnormalities. RTT is primarily caused by the genetic mutation of the Mecp2 gene. Initially considered a neuronal disease, recent research shows that glial dysfunction contributes to the RTT disease phenotype.

Mutual action by Gγ and Gβ for optimal activation of GIRK channels in a channel subunit-specific manner.

The tetrameric G protein-gated K channels (GIRKs) mediate inhibitory effects of neurotransmitters that activate G-coupled receptors. GIRKs are activated by binding of the Gβγ dimer, via contacts with Gβ. Gγ underlies membrane targeting of Gβγ, but has not been implicated in channel gating.

MeCP2 Deficiency Leads to Loss of Glial Kir4.1.

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder usually caused by mutations in methyl-CpG-binding protein 2 (MeCP2). RTT is typified by apparently normal development until 6-18 mo of age, when motor and communicative skills regress and hand stereotypies, autonomic symptoms, and seizures present. Restoration of MeCP2 function selectively to astrocytes reversed several deficits in a murine model of RTT, but the mechanism of this rescue is unknown.

Collision coupling in the GABA receptor-G protein-GIRK signaling cascade.

The signaling cascade comprising the 4-aminobutyrate(B) receptor (GABA R), G protein and the G protein-gated K channel (GIRK) mediates neuronal inhibition in the brain. Precoupling between components of the pathway (within a permanent macromolecular complex) has been proposed, but this remains debatable. We investigated this mechanism in Xenopus oocytes by varying the expression of the GABA R.

A Quantitative Model of the GIRK1/2 Channel Reveals That Its Basal and Evoked Activities Are Controlled by Unequal Stoichiometry of Gα and Gβγ.

G protein-gated K+ channels (GIRK; Kir3), activated by Gβγ subunits derived from Gi/o proteins, regulate heartbeat and neuronal excitability and plasticity. Both neurotransmitter-evoked (Ievoked) and neurotransmitter-independent basal (Ibasal) GIRK activities are physiologically important, but mechanisms of Ibasal and its relation to Ievoked are unclear. We have previously shown for heterologously expressed neuronal GIRK1/2, and now show for native GIRK in hippocampal neurons, that Ibasal and Ievoked are interrelated: the extent of activation by neurotransmitter (activation index, Ra) is inversely related to Ibasal.

The Roles of Gβγ and Gα in Gating and Regulation of GIRK Channels.

G protein-gated K(+) (GIRK, or Kir3) channels mediate inhibitory neurotransmission via G protein-coupled receptors (GPCRs) in heart and brain. The signaling cascade involves activation of GPCR by an agonist, activation of a G protein followed by rearrangement or dissociation of activated Gα(GTP) from Gβγ, and activation of GIRK by Gβγ. Gβγ is the main transducer of GPCR activating signal to the GIRK channel.

Recruitment of Gβγ controls the basal activity of G-protein coupled inwardly rectifying potassium (GIRK) channels: crucial role of distal C terminus of GIRK1.

The G-protein coupled inwardly rectifying potassium (GIRK, or Kir3) channels are important mediators of inhibitory neurotransmission via activation of G-protein coupled receptors (GPCRs). GIRK channels are tetramers comprising combinations of subunits (GIRK1-4), activated by direct binding of the Gβγ subunit of Gi/o proteins. Heterologously expressed GIRK1/2 exhibit high, Gβγ-dependent basal currents (Ibasal) and a modest activation by GPCR or coexpressed Gβγ.

Dual regulation of G proteins and the G-protein-activated K+ channels by lithium.

Lithium (Li(+)) is widely used to treat bipolar disorder (BPD). Cellular targets of Li(+), such as glycogen synthase kinase 3β (GSK3β) and G proteins, have long been implicated in BPD etiology; however, recent genetic studies link BPD to other proteins, particularly ion channels. Li(+) affects neuronal excitability, but the underlying mechanisms and the relevance to putative BPD targets are unknown.