Glycine-induced activation of GPR158 increases the intrinsic excitability of medium spiny neurons in the nucleus accumbens.

Autor: Aceto G; Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome, 00168, Italy.; Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, 00168, Italy., Nardella L; Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, 00168, Italy., Nanni S; Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome, 00168, Italy.; Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, 00168, Italy., Pecci V; Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, 00168, Italy., Bertozzi A; Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, 00168, Italy.; Istituto di Analisi dei Sistemi ed Informatica 'Antonio Ruberti', National Research Council, Rome, Italy., Nutarelli S; Department of Life Science and Public Health, Università Cattolica del Sacro Cuore, Rome, 00168, Italy., Viscomi MT; Department of Life Science and Public Health, Università Cattolica del Sacro Cuore, Rome, 00168, Italy., Colussi C; Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome, 00168, Italy.; Istituto di Analisi dei Sistemi ed Informatica 'Antonio Ruberti', National Research Council, Rome, Italy., D'Ascenzo M; Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome, 00168, Italy. marcello.dascenzo@unicatt.it.; Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, 00168, Italy. marcello.dascenzo@unicatt.it., Grassi C; Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome, 00168, Italy.; Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, 00168, Italy.
Jazyk: angličtina
Zdroj: Cellular and molecular life sciences : CMLS [Cell Mol Life Sci] 2024 Jun 17; Vol. 81 (1), pp. 268. Date of Electronic Publication: 2024 Jun 17.
DOI: 10.1007/s00018-024-05260-w
Abstrakt: It has been recently established that GPR158, a class C orphan G protein-coupled receptor, serves as a metabotropic glycine receptor. GPR158 is highly expressed in the nucleus accumbens (NAc), a major input structure of the basal ganglia that integrates information from cortical and subcortical structures to mediate goal-directed behaviors. However, whether glycine modulates neuronal activity in the NAc through GPR158 activation has not been investigated yet. Using whole-cell patch-clamp recordings, we found that glycine-dependent activation of GPR158 increased the firing rate of NAc medium spiny neurons (MSNs) while it failed to significantly affect the excitability of cholinergic interneurons (CIN). In MSNs GPR158 activation reduced the latency to fire, increased the action potential half-width, and reduced action potential afterhyperpolarization, effects that are all consistent with negative modulation of potassium M-currents, that in the central nervous system are mainly carried out by Kv7/KCNQ-channels. Indeed, we found that the GPR158-induced increase in MSN excitability was associated with decreased M-current amplitude, and selective pharmacological inhibition of the M-current mimicked and occluded the effects of GPR158 activation. In addition, when the protein kinase A (PKA) or extracellular signal-regulated kinase (ERK) signaling was pharmacologically blocked, modulation of MSN excitability by GPR158 activation was suppressed. Moreover, GPR158 activation increased the phosphorylation of ERK and Kv7.2 serine residues. Collectively, our findings suggest that GPR158/PKA/ERK signaling controls MSN excitability via Kv7.2 modulation. Glycine-dependent activation of GPR158 may significantly affect MSN firing in vivo, thus potentially mediating specific aspects of goal-induced behaviors.
(© 2024. The Author(s).)
Databáze: MEDLINE
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