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

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 D-2-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(alpha q/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 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 NTS1/2 and mGluR I in DAergic neurons of rat midbrain by tuning the degree of NTS1/2 desensitization.