About this Research Topic

Background

G protein-coupled receptors (GPCRs) are the most comprehensively researched drug targets. Drugs that aim for GPCRs comprise approximately 27% of the international market share of therapeutic drugs, with combined sales for 2011–2015 of ~US$ 890 billion. One of the most intensively studied effector families of G-proteins are ion channels. Measuring ionic currents utilizing whole cell and patch electrophysiological methods provide unique opportunity to study protein-protein interactions with high amplitude and temporal resolution. Moreover, utilization of heterologous expression systems enables the researchers to control systems under investigation both from the point of view of interacting proteins and also their density.

Two well studied effectors of G-proteins are GIRK (G protein activated inward rectifier potassium channels) and N-type voltage gated Ca2+ channel (Cav2.2). The interaction of GIRK with Gβγ causes multiple allosteric changes in GIRK channel structure, which are transferred to channel gate leading to its opening. Moreover, direct interaction of GIRK channels with Gα subunits of Gi/o proteins has also been extensively studied.

On the other hand Gβγ binding to α1 subunit of N-type Ca2+ channels shifts the channel from “willing” to “reluctant” gating mode thus decreasing the channel open probability. Multiple modulatory factors are involved in GIRK-Gβγ interaction such as PIP2 and Na+ ions. The major modulator of Gβγ-Cav2.2 interaction is voltage, i.e. positive voltage shifts can decrease Gβγ affinity thus leading to voltage-dependent facilitation of Ca2+ currents.

In addition to above mentioned Gβγ effectors there is growing line of evidence of other ion channels being directly modulated by direct interaction with G-protein subunits. Among others TRPM3 channel activity decreases as a result of direct binding of Gβγ and cryo-EM structure of TRPM3- Gβγ complex has been recently published.

It must be emphasized that, despite vast research effort invested in studies of direct G-proteins- channels interaction still the unknown is by far larger than known in this field. For instance, our understanding of GIRK-Gβγ is still incomplete both from structural point of view (most of the know crystal structures of GIRK- Gβγ are based on truncated GIRK channels) and also from the point of view of structure-function relationship interpretation (i.e. the affinities of GIRK-Gβγ interactions demonstrated by various methods range from tens of nM to hundreds of µM). Moreover, kinetic model of GIRK activation by Gβγ is still unclear in light of competing but not mutually exclusive 4 Gβγ- mediated concerted scheme of GIRK1/2 and GIRK1/4 activation versus graded contribution model.

Moreover, there is no known structure of N-type Ca2+ channel and Gβγ. Additionally, other voltage gated Ga2+ channels have been shown to interact with Gβγ such as Cav3.2 channels for which reduction of open probability has been demonstrated on activation of D1R dopamine receptors without involvement of any second messenger. Furthermore, electrophysiological analysis of TRPM3- Gβγ interaction yields sub-micromolar affinity while cryo-EM structures show rather loose attachment of Gβγ to its channel binding site.

In this Research Topic, we welcome contributions in the form of original research, review, mini review, case report, hypothesis and theory, perspective, both experimental and computational studies that cover, but are not limited to, following themes:

-Direct interaction of G-protein subunits with ion channels;
-Effect of mutations in G-proteins on health and disease conditions mediated via change in interaction with ion channels;
-Structural analysis of G-protein interaction with ion channels;
-Novel methods and therapeutic strategies in research of G-proteins and ion channels interactions.

Topic Editors declare no conflict of interest.

Keywords: Ion channel, GPCR, G-protein, kinetics, structural modeling, electrophysiology, signal transduction, G protein-coupled receptor

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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