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

Tabak, Galit; Keren-Raifman, Tal; Kahanovitch, Uri; Dascal, Nathan

doi:10.1038/s41598-018-36833-y

Cited by 10 publications

(11 citation statements)

References 86 publications

(116 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is important to note that our study has not investigated the role of Gγ in Kv7.4 channel regulation and this could well be an important determinant as described recently for Kir channels (Tabak et al, 2019). Certainly, in overexpression studies the Gγ natively expressed in these cells could be a determinant in the behavior of the Gβ subunits expressed.…”

Section: Gβγ Specificitymentioning

confidence: 87%

The Gβ1 and Gβ3 Subunits Differentially Regulate Rat Vascular Kv7 Channels

Greenwood

Stott

2020

Front. Physiol.

View full text Add to dashboard Cite

Within the vasculature Kv7 channels are key regulators of basal tone and contribute to a variety of receptor mediated vasorelaxants. The Kv7.4 isoform, abundant within the vasculature, is key to these processes and was recently shown to have an obligatory requirement of G-protein βγ subunits for its voltage dependent activity. There is an increasing appreciation that with 5 Gβ subunits and 12 Gγ subunits described in mammalian cells that different Gβ x γ x combinations can confer selectivity in Gβγ effector stimulation. Therefore, we aimed to characterize the Gβ subunit(s) which basally regulate Kv7.4 channels and native vascular Kv7 channels. In Chinese Hamster Ovary cells overexpressing Kv7.4 and different Gβx subunits only Gβ1, Gβ3, and Gβ5 enhanced Kv7.4 currents, increasing the activation kinetics and negatively shifting the voltage dependence of activation. In isolated rat renal artery myocytes, proximity ligation assay detected an interaction of Kv7.4 with Gβ1 and Gβ3 subunits, but not other isoforms. Morpholino directed knockdown of Gβ1 in rat renal arteries did not alter Kv7 dependent currents but reduced Kv7.4 protein expression. Knockdown of Gβ3 in rat renal arteries resulted in decreased basal K + currents which were not sensitive to pharmacological inhibition of Kv7 channels. These studies implicate the Gβ1 subunit in the synthesis or stability of Kv7.4 proteins, whilst revealing that the Gβ3 isoform is responsible for the basal activity of Kv7 channels in native rat renal myocytes. These findings demonstrate that different Gβ subunits have important individual roles in ion channel regulation.

show abstract

Section: Gβγ Specificitymentioning

confidence: 87%

The Gβ1 and Gβ3 Subunits Differentially Regulate Rat Vascular Kv7 Channels

Greenwood

Stott

2020

Front. Physiol.

View full text Add to dashboard Cite

show abstract

“…cDNA constructs of GIRK subunits, Gβ 1 , Gγ 2 , M2R, YFP-GIRK1 were described in detail in previous publications (see ( Tabak et al, 2019 ) for a detailed list). Fluorescent proteins (CFP and YFP) contained the A207K mutation to prevent dimerization ( Zacharias et al, 2002 ).…”

Section: Methodsmentioning

confidence: 99%

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

Berlin¹,

Artzy

Handklo-Jamal

et al. 2020

Front. Pharmacol.

Self Cite

View full text Add to dashboard Cite

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 (Gabg), opening of the channel is obtained by direct binding of Gbg subunits. Interestingly, GIRKs are solely activated by Gbg subunits released from Ga i/ocoupled GPCRs, despite the fact that all receptor types, for instance Ga q-coupled, are also able to provide Gbg subunits. It is proposed that this specificity and fast kinetics of activation stem from pre-coupling (or pre-assembly) of proteins within this signaling cascade. However, many studies, including our own, point towards a diffusion-limited mechanism, namely collision coupling. Here, we set out to address this long-standing question by combining electrophysiology, imaging, and mathematical modeling. Muscarinic-2 receptors (M2R) and neuronal GIRK1/2 channels were coexpressed in Xenopus laevis oocytes, where we monitored protein surface expression, current amplitude, and activation kinetics. Densities of expressed M2R were assessed using a fluorescently labeled GIRK channel as a molecular ruler. We then incorporated our results, along with available kinetic data reported for the G-protein cycle and for GIRK1/2 activation, to generate a comprehensive mathematical model for the M2R-G-protein-GIRK1/2 signaling cascade. We find that, without assuming any irreversible interactions, our collision coupling kinetic model faithfully reproduces the rate of channel activation, the changes in agonist-evoked currents and the acceleration of channel activation by increased receptor densities.

show abstract

“…Such variable onset delays can be observed in certain species such as rabbits and ferrets [12,71] but there are other species such as mice that exhibit a fixed onset delay of conditional eye-blink response [72]. Our models can reproduce such a behavior as well if the individual G-protein subunits are strongly interacting with each other-as sometimes observed experimentally [73]-such that in (Eq 2) the 4 units of G-protein subunits, G βγ , give rise to a term h girk instead of h 4 girk . This is shown in the bottom panels of (Fig 8) using the very slightly modified parameter values given in S4 Table…”

Section: Plos Onementioning

confidence: 57%

“…Both mathematical models assume simple activation and deactivation dynamics for the G α and G βγ subunits depending on receptor’s activity even though individual G-protein subunits have been shown to modulate the GIRK ion channel gating dynamics [ 73 ]. Due to the slower dynamics of the modulation compared to the conditional response, we have neglected this here.…”

Section: Discussionmentioning

confidence: 99%

A biochemical mechanism for time-encoding memory formation within individual synapses of Purkinje cells

et al. 2021

View full text Add to dashboard Cite

Within the classical eye-blink conditioning, Purkinje cells within the cerebellum are known to suppress their tonic firing rates for a well defined time period in response to the conditional stimulus after training. The temporal profile of the drop in tonic firing rate, i.e., the onset and the duration, depend upon the time interval between the onsets of the conditional and unconditional training stimuli. Direct stimulation of parallel fibers and climbing fiber by electrodes was found to be sufficient to reproduce the same characteristic drop in the firing rate of the Purkinje cell. In addition, the specific metabotropic glutamate-based receptor type 7 (mGluR7) was found responsible for the initiation of the response, suggesting an intrinsic mechanism within the Purkinje cell for the temporal learning. In an attempt to look for a mechanism for time-encoding memory formation within individual Purkinje cells, we propose a biochemical mechanism based on recent experimental findings. The proposed mechanism tries to answer key aspects of the “Coding problem” of Neuroscience by focusing on the Purkinje cell’s ability to encode time intervals through training. According to the proposed mechanism, the time memory is encoded within the dynamics of a set of proteins—mGluR7, G-protein, G-protein coupled Inward Rectifier Potassium ion channel, Protein Kinase A, Protein Phosphatase 1 and other associated biomolecules—which self-organize themselves into a protein complex. The intrinsic dynamics of these protein complexes can differ and thus can encode different time durations. Based on their amount and their collective dynamics within individual synapses, the Purkinje cell is able to suppress its own tonic firing rate for a specific time interval. The time memory is encoded within the effective dynamics of the biochemical reactions and altering these dynamics means storing a different time memory. The proposed mechanism is verified by both a minimal and a more comprehensive mathematical model of the conditional response behavior of the Purkinje cell and corresponding dynamical simulations of the involved biomolecules, yielding testable experimental predictions.

show abstract

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

Cited by 10 publications

References 86 publications

The Gβ1 and Gβ3 Subunits Differentially Regulate Rat Vascular Kv7 Channels

The Gβ1 and Gβ3 Subunits Differentially Regulate Rat Vascular Kv7 Channels

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

A biochemical mechanism for time-encoding memory formation within individual synapses of Purkinje cells

Contact Info

Product

Resources

About