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

Research output: Contribution to journalArticle

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 Gαq/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 (NTS1/2), as revealed by pharmacological analysis. Activation of other metabotropic receptors, such as muscarinic and GABAB, 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 NTS1/2 and mGluR I in DAergic neurons of rat midbrain by tuning the degree of NTS1/2 desensitization.

Original languageEnglish
Pages (from-to)76-88
Number of pages13
JournalNeuropharmacology
Volume155
DOIs
Publication statusPublished - Sep 1 2019

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Neurotensin Receptors
G-Protein-Coupled Receptor Kinases
Neurotensin
Metabotropic Glutamate Receptors
Dopaminergic Neurons
Substantia Nigra
G-Protein-Coupled Receptor Kinase 3
G-Protein-Coupled Receptor Kinase 2
Clathrin
Ventral Tegmental Area
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Neurotransmitter Receptor
Calcineurin
Mitogen-Activated Protein Kinase Kinases
Presynaptic Terminals
N-Methylaspartate
Mesencephalon
Endocytosis
Cholinergic Agents
Neurotransmitter Agents

Keywords

  • Calcium
  • DHPG
  • Electrophysiology
  • GRK
  • Microfluorometry

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

Cite this

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title = "Neurotensin receptors inhibit mGluR I responses in nigral dopaminergic neurons via a process that undergoes functional desensitization by G-protein coupled receptor kinases",
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 Gαq/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 (NTS1/2), as revealed by pharmacological analysis. Activation of other metabotropic receptors, such as muscarinic and GABAB, 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 NTS1/2 and mGluR I in DAergic neurons of rat midbrain by tuning the degree of NTS1/2 desensitization.",
keywords = "Calcium, DHPG, Electrophysiology, GRK, Microfluorometry",
author = "Alessandro Martini and Alberto Cordella and Antonio Pisani and Mercuri, {Nicola B.} and Ezia Guatteo",
year = "2019",
month = "9",
day = "1",
doi = "10.1016/j.neuropharm.2019.05.026",
language = "English",
volume = "155",
pages = "76--88",
journal = "Neuropharmacology",
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TY - JOUR

T1 - Neurotensin receptors inhibit mGluR I responses in nigral dopaminergic neurons via a process that undergoes functional desensitization by G-protein coupled receptor kinases

AU - Martini, Alessandro

AU - Cordella, Alberto

AU - Pisani, Antonio

AU - Mercuri, Nicola B.

AU - Guatteo, Ezia

PY - 2019/9/1

Y1 - 2019/9/1

N2 - 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 Gαq/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 (NTS1/2), as revealed by pharmacological analysis. Activation of other metabotropic receptors, such as muscarinic and GABAB, 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 NTS1/2 and mGluR I in DAergic neurons of rat midbrain by tuning the degree of NTS1/2 desensitization.

AB - 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 Gαq/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 (NTS1/2), as revealed by pharmacological analysis. Activation of other metabotropic receptors, such as muscarinic and GABAB, 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 NTS1/2 and mGluR I in DAergic neurons of rat midbrain by tuning the degree of NTS1/2 desensitization.

KW - Calcium

KW - DHPG

KW - Electrophysiology

KW - GRK

KW - Microfluorometry

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U2 - 10.1016/j.neuropharm.2019.05.026

DO - 10.1016/j.neuropharm.2019.05.026

M3 - Article

VL - 155

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EP - 88

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JF - Neuropharmacology

SN - 0028-3908

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