NEUROTENSIN IN CENTRAL NEUROTRANSMISSION

MARÍA GRACIELA LÓPEZ ORDIERES; GEORGINA RODRÍGUEZ DE LORES ARNAIZ

Function of Neuropeptides at Central Nervous System

Research Signpost (ed. G. Rodríguez de Lores Arnaiz)

Lugar: Trivandrum, Kerala, India ; Año: 2009; p. 1 - 30

Neurotensin is a tridecapeptide widely distributed throughout the brain and the gastrointestinal tract. This peptide exerts a wide spectrum of effects at both central and peripheral nervous systems. At central nervous system, neurotensin is involved in diverse physiological processes, including locomotion, reward, modulation of stress and pain, as well as in pathological situations such as depression and drug addiction.    Neurotensin can act as a neuromodulator, a neurotransmitter as well as an endocrine modulator. In the latter case, it acts as a trophic factor in normal and neoplastic tissues and is involved in paracrine and autocrine functions.   Neurotensin binds to a group of receptors. Two of them, termed NTS1 and NTS2 respectively bind the peptide with high and low affinity, and are G-protein-coupled receptors. Neurotensin acts as an agonist in all NTS1 mediated pathways, whereas it exerts either agonist or antagonist activity, according to the NTS2-mediated pathway involved. The high affinity receptor type is sensitive to Na+ and GTP, both of which decrease its affinity for the peptide; in turn, the low affinity type is less sensitive to Na+ and insensitive to GTP. Both types correspond to seven transmembrane domain G protein-coupled receptors. The high affinity receptor has been linked to a variety of transductional effects including stimulation of cGMP and inositol phosphate production, as well as Ca2+ mobilization.    Most of the known central and peripheral effects of neurotensin are mediated through NTS1 receptor, which are prevented by SR 48692, a non-peptidic antagonist. NTS2 receptor is involved in visceral nociception and is implied in analgesic responses of neurotensin after its central administration. For this receptor, levocabastine behaves as a partial agonist.   Besides NTS1 and NTS2 receptors, another two receptor types, NTS3 /sortilin and nts4 / SorLA receptors, are mainly localized intracelullarly.   Enzyme catabolism and receptor internalization seem to be involved in removal and / or inactivation of neurotensin. Degradation of this peptide occurs by a combination of three Zn metallo-endopeptidases: endopeptidases 24.11, 24.15 and 24.16.   In response to extracellular ligands, molecular mechanisms involving internalization and recycling take place.   Diverse findings indicate the participation of neurotensin in signal transduction processes through activation of NTS1, NTS2 or NTS3 receptors.   Neurotensin stimulates ERK signaling pathway, which in turn activates downstream transcription factors, leading to proliferation. Other examples are Ras activation, phosphatidylinositol 3-kinase (PI 3-kinase), mitogen-activated protein (MAP) kinase pathways stimulation, as well as MAP kinases ERK1/2 enhancement.   Relationships between neurotensinergic system with other neurotransmitter systems are observed. A functional interaction between neurotensin and dopamine systems seems to occur. Besides, neurotensin agonists most likely produce some of their antipsychotic-like effects by modulation of neurotransmitter systems other than dopaminergic one, including cholinergic, serotonergic, opioid and aminoacidergic systems, among others.   Neurotensin inhibits synaptosomal membrane Na+, K+-ATPase activity, an effect fully blocked by SR 48692, indicating the involvement of NTS1 receptor. This finding suggests the participation of neurotensin in the regulation of ionic equilibrium through neuronal membranes.   Neurotensinergic circuits seem to mediate some of the mechanisms of action of antipsychotic drugs, the rewarding and / or sensitizing properties of abuse drugs. However, neurotensin is most likely involved in schizophrenia, Parkinson disease, psychosis and drug addiction.