Co-activation of GPCRs facilitate GIRK-dependent current.

Autor: Condon AF; The Vollum Institute, Oregon Health Sciences University, Portland, USA., Asad N; New York University Abu Dhabi, Saadiyat Island, Abu Dhabi, United Arab Emirates., Dore TM; New York University Abu Dhabi, Saadiyat Island, Abu Dhabi, United Arab Emirates., Williams JT; The Vollum Institute, Oregon Health Sciences University, Portland, USA.
Jazyk: angličtina
Zdroj: The Journal of physiology [J Physiol] 2022 Nov; Vol. 600 (22), pp. 4881-4895. Date of Electronic Publication: 2022 Oct 06.
DOI: 10.1113/JP283590
Abstrakt: The activity of dopamine neurons is dependent on both intrinsic properties and afferent projections. One potent form of inhibition is mediated by the activation of two inhibitory G protein-coupled receptors, D2 and GABA B receptors. Each of these receptors activates G protein-coupled inwardly rectifying potassium (GIRK) channels. Recordings in brain slices have shown that co-activation using saturating concentrations of agonists results in occlusion of the GIRK current. The present study examined the interaction between D2 and GABA B receptors using transient applications of sub-saturating concentrations of agonists where the co-application of one agonist resulted in both facilitation and inhibition (desensitization) of the other. The heterologous facilitation was modelled based on the known cooperative interaction between the G protein βγ subunits and GIRK channels. The results indicate that a low tonic level of G βγ results in facilitation of GIRK current and a high level of G βγ results in occlusion. The kinetics of the current induced by transient receptor activation is prolonged in each case. The results suggest that the cooperative interaction between G βγ subunits and GIRK channels determines both the amplitude and kinetics of GPCR-dependent current. KEY POINTS: Inhibitory D2 and GABA B receptors modulate dopamine neuron activity through shared G protein-coupled inwardly rectifying potassium (GIRK) channels. This study reports robust bidirectional interactions between these two converging receptor pathways. Coincident activation of D2 and GABA B receptors leads to facilitation of GIRK channel currents, augmenting both amplitude and prolonging the duration of phasic responses. Activation of either D2 or GABA B receptors also acutely desensitized the GIRK channel current induced by D2 receptor activation that rapidly recovers following termination of desensitizing stimulus. Results demonstrate that the activity of either G protein-coupled receptor system must be considered in the context of other G protein-coupled receptors.
(© 2022 The Authors. The Journal of Physiology © 2022 The Physiological Society.)
Databáze: MEDLINE
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