TY - JOUR
T1 - Neurotensin excitation of serotonergic neurons in the rat nucleus raphe magnus
T2 - Ionic and molecular mechanisms
AU - Li, Allen H.
AU - Yeh, Tu Hsueh
AU - Tan, Peter P.
AU - Hwang, Hwa Min
AU - Wang, Hung Li
N1 - Funding Information:
This work was supported by the fund from the National Science Council (NSC89-2320-B-182-057) and the Chang Gung Medical Research Foundation (CMRP 555).
PY - 2001/6/23
Y1 - 2001/6/23
N2 - To understand the cellular and molecular mechanisms by which neurotensin (NT) induces an analgesic effect in the nucleus raphe magnus (NRM), whole-cell patch-clamp recordings were performed to investigate the electrophysiological effects of NT on acutely dissociated NRM neurons. Two subtypes of neurons, primary serotonergic and secondary non-serotonergic cells, were identified from acutely isolated NRM neurons. During current-clamp recordings, NT depolarized NRM serotonergic neurons and evoked action potentials. Voltage-clamp recordings showed that NT excited serotonergic neurons by enhancing a voltage-insensitive and non-selective cationic conductance. Both SR48692, a selective antagonist of subtype 1 neurotensin receptor (NTR-1), and SR 142948A, a non-selective antagonist of NTR-1 and subtype 2 neurotensin receptor (NTR-2), failed to prevent neurotensin from exciting NRM serotonergic neurons. NT-evoked cationic current was inhibited by the intracellular administration of GDP-β-S. NT failed to induce cationic currents after dialyzing serotonergic neurons with the anti-Gαq/11 antibody. Cellular Ca2+ imaging study using fura-2 showed that NT induced the calcium release from the intracellular store. NT-evoked current was blocked after the internal perfusion of heparin, an IP3 receptor antagonist, or BAPTA, a fast Ca2+ chelator. It is concluded that neurotensin enhancement of the cationic conductance of NRM serotonergic neurons is mediated by a novel subtype of neurotensin receptors. The coupling mechanism via Gαq/11 proteins is likely to involve the generation of IP3, and subsequent IP3-evoked Ca2+ release from intracellular stores results in activating the non-selective cationic conductance.
AB - To understand the cellular and molecular mechanisms by which neurotensin (NT) induces an analgesic effect in the nucleus raphe magnus (NRM), whole-cell patch-clamp recordings were performed to investigate the electrophysiological effects of NT on acutely dissociated NRM neurons. Two subtypes of neurons, primary serotonergic and secondary non-serotonergic cells, were identified from acutely isolated NRM neurons. During current-clamp recordings, NT depolarized NRM serotonergic neurons and evoked action potentials. Voltage-clamp recordings showed that NT excited serotonergic neurons by enhancing a voltage-insensitive and non-selective cationic conductance. Both SR48692, a selective antagonist of subtype 1 neurotensin receptor (NTR-1), and SR 142948A, a non-selective antagonist of NTR-1 and subtype 2 neurotensin receptor (NTR-2), failed to prevent neurotensin from exciting NRM serotonergic neurons. NT-evoked cationic current was inhibited by the intracellular administration of GDP-β-S. NT failed to induce cationic currents after dialyzing serotonergic neurons with the anti-Gαq/11 antibody. Cellular Ca2+ imaging study using fura-2 showed that NT induced the calcium release from the intracellular store. NT-evoked current was blocked after the internal perfusion of heparin, an IP3 receptor antagonist, or BAPTA, a fast Ca2+ chelator. It is concluded that neurotensin enhancement of the cationic conductance of NRM serotonergic neurons is mediated by a novel subtype of neurotensin receptors. The coupling mechanism via Gαq/11 proteins is likely to involve the generation of IP3, and subsequent IP3-evoked Ca2+ release from intracellular stores results in activating the non-selective cationic conductance.
KW - G proteins
KW - Inositol (1,4,5) trisphosphate
KW - Neurotensin
KW - Non-selective cationic currents
KW - Nucleus raphe magnus
KW - Serotonergic neuron
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U2 - 10.1016/S0028-3908(01)00030-2
DO - 10.1016/S0028-3908(01)00030-2
M3 - Article
C2 - 11406199
AN - SCOPUS:0034991041
SN - 0028-3908
VL - 40
SP - 1073
EP - 1083
JO - Neuropharmacology
JF - Neuropharmacology
IS - 8
ER -