Neurotensin receptors inhibit mGluR I responses in nigral dopaminergic neurons via a process that undergoes functional desensitization by G-protein coupled receptor kinases

Alessandro Martini; Alberto Cordella; Antonio Pisani; Nicola B Mercuri; Ezia Guatteo

doi:10.1016/j.neuropharm.2019.05.026

Neurotensin receptors inhibit mGluR I responses in nigral dopaminergic neurons via a process that undergoes functional desensitization by G-protein coupled receptor kinases

Neuropharmacology. 2019 Sep 1:155:76-88. doi: 10.1016/j.neuropharm.2019.05.026. Epub 2019 May 22.

Authors

Alessandro Martini¹, Alberto Cordella¹, Antonio Pisani², Nicola B Mercuri³, Ezia Guatteo⁴

Affiliations

¹ IRCCS Fondazione Santa Lucia, Experimental Neurology, Via del Fosso di Fiorano 64, 00143, Rome, Italy.
² IRCCS Fondazione Santa Lucia, Experimental Neurology, Via del Fosso di Fiorano 64, 00143, Rome, Italy; University of Rome Tor Vergata, Department of Systems Medicine, Via Montpellier 1, 00133, Rome, Italy.
³ IRCCS Fondazione Santa Lucia, Experimental Neurology, Via del Fosso di Fiorano 64, 00143, Rome, Italy; University of Rome Tor Vergata, Department of Systems Medicine, Via Montpellier 1, 00133, Rome, Italy. Electronic address: mercurin@med.uniroma2.it.
⁴ University of Naples 'Parthenope', Department of Motor Science and Wellness, Via Medina 40, 80133, Naples, Italy; IRCCS Fondazione Santa Lucia, Experimental Neurology, Via del Fosso di Fiorano 64, 00143, Rome, Italy. Electronic address: ezia.guatteo@uniparthenope.it.

PMID: 31128122
DOI: 10.1016/j.neuropharm.2019.05.026

Abstract

Neurotensin (NT) is a 13-amino acid peptide acting as a neuromodulator in the CNS. NT immunoreactive cell bodies, synaptic terminals and receptors (NTS) are intimately associated with the dopaminergic system. In fact, NT exerts a stimulatory action on the dopaminergic (DAergic) neurons of substantia nigra pars compacta (SNpc) and ventral tegmental area by activating a mixed cation conductance, reducing D₂-autoinhibition and modulating NMDA and AMPA transmission. In the present work, we describe an inhibitory effect of NT on metabotropic glutamate receptor I (mGluR I) actions in rat SNpc DAergic neurons. NTS and mGluR I share the same G_αq/11-PLC-IP₃-Ca²⁺ intracellular pathway which causes either activation of unspecific cationic conductance or intracellular Ca²⁺ accumulation. We find that NT inhibits both inward current and the associated intracellular calcium elevation, elicited by the selective mGluR I agonist S-DHPG, in a concentration-dependent manner. This effect is mediated by type 1/2 NT receptors (NTS_1/2), as revealed by pharmacological analysis. Activation of other metabotropic receptors, such as muscarinic and GABA_B, does not inhibit mGluR I inward currents. PKC, MEK 1-2, calcineurin, clathrin-dependent endocytosis and intracellular Ca²⁺ elevation are not involved in the NT-mediated modulation of mGluR I responses. Interestingly, inhibition of G-protein coupled receptor kinases (GRKs) 2/3 exacerbates the NT-induced mGluR I inhibition while sustaining the NT-induced inward current during repeated agonist stimulation. These data suggest that GRKs are key molecules regulating either the NT excitation or the cross-talk between NTS_1/2 and mGluR I in DAergic neurons of rat midbrain by tuning the degree of NTS_1/2 desensitization.

Keywords: Calcium; DHPG; Electrophysiology; GRK; Microfluorometry.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Dopaminergic Neurons / drug effects
Dopaminergic Neurons / metabolism*
Female
G-Protein-Coupled Receptor Kinases / metabolism*
Male
Neurotensin / pharmacology*
Organ Culture Techniques
Rats
Rats, Wistar
Receptors, Metabotropic Glutamate / antagonists & inhibitors
Receptors, Metabotropic Glutamate / metabolism*
Receptors, Neurotensin / metabolism*
Substantia Nigra / drug effects
Substantia Nigra / metabolism*

Substances

Receptors, Metabotropic Glutamate
Receptors, Neurotensin
metabotropic glutamate receptor type 1
Neurotensin
G-Protein-Coupled Receptor Kinases