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1.
Front Endocrinol (Lausanne) ; 13: 1029210, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36457557

RESUMO

Glutamate is one of the most abundant amino acids in the blood. Besides its role as a neurotransmitter in the brain, it is a key substrate in several metabolic pathways and a primary messenger that acts through its receptors outside the central nervous system (CNS). The two main types of glutamate receptors, ionotropic and metabotropic, are well characterized in CNS and have been recently analyzed for their roles in non-neural organs. Glutamate receptor expression may be particularly important for tumor growth in organs with high concentrations of glutamate and might also influence the propensity of such tumors to set metastases in glutamate-rich organs, such as the liver. The study of glutamate transporters has also acquired relevance in the physiology and pathologies outside the CNS, especially in the field of cancer research. In this review, we address the recent findings about the expression of glutamatergic system components, such as receptors and transporters, their role in the physiology and pathology of cancer in non-neural organs, and their possible use as biomarkers and therapeutic targets.


Assuntos
Neoplasias , Humanos , Biomarcadores , Glutamatos , Sistema Nervoso Central , Aminoácidos
2.
Int J Biochem Cell Biol ; 100: 1-10, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29704625

RESUMO

The activity of tricyclic antidepressants (TCAs) at α7 and α9α10 nicotinic acetylcholine receptors (AChRs) as well as at hippocampal α7-containing (i.e., α7*) AChRs is determined by using Ca2+ influx and electrophysiological recordings. To determine the inhibitory mechanisms, additional functional tests and molecular docking experiments are performed. The results established that TCAs (a) inhibit Ca2+ influx in GH3-α7 cells with the following potency (IC50 in µM) rank: amitriptyline (2.7 ±â€¯0.3) > doxepin (5.9 ±â€¯1.1) ∼ imipramine (6.6 ±â€¯1.0). Interestingly, imipramine inhibits hippocampal α7* AChRs (42.2 ±â€¯8.5 µM) in a noncompetitive and voltage-dependent manner, whereas it inhibits α9α10 AChRs (0.53 ±â€¯0.05 µM) in a competitive and voltage-independent manner, and (b) inhibit [3H]imipramine binding to resting α7 AChRs with the following affinity rank (IC50 in µM): imipramine (1.6 ±â€¯0.2) > amitriptyline (2.4 ±â€¯0.3) > doxepin (4.9 ±â€¯0.6), whereas imipramine's affinity was no significantly different to that for the desensitized state. The molecular docking and functional results support the notion that imipramine noncompetitively inhibits α7 AChRs by interacting with two overlapping luminal sites, whereas it competitively inhibits α9α10 AChRs by interacting with the orthosteric sites. Collectively our data indicate that TCAs inhibit α7, α9α10, and hippocampal α7* AChRs at clinically relevant concentrations and by different mechanisms of action.


Assuntos
Antidepressivos Tricíclicos/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Receptores Nicotínicos/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/antagonistas & inibidores , Animais , Antidepressivos Tricíclicos/metabolismo , Sítios de Ligação , Linhagem Celular , Interações Medicamentosas , Imipramina/farmacologia , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Conformação Proteica , Ratos , Receptores Nicotínicos/química , Termodinâmica , Receptor Nicotínico de Acetilcolina alfa7/química , Receptor Nicotínico de Acetilcolina alfa7/metabolismo
3.
Neurosci Lett ; 665: 246-251, 2018 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-29225093

RESUMO

Nicotinic acetylcholine receptors (nAChRs) and zinc are associated with regulation of mood and related disorders. In addition, several antidepressants inhibit muscle and neuronal nAChRs and zinc potentiates inhibitory actions of them. Moreover, mirtazapine (a noradrenergic, serotonergic and histaminergic antidepressant) inhibits muscarinic AChRs and its effects on nAChRs are unknown. Therefore, we studied the modulation of muscle α1ß1γd nAChRs expressed in oocytes and native α7-containing nAChRs in hippocampal interneurons by mirtazapine and/or zinc, using voltage-clamp techniques. The currents elicited by ACh in oocytes (at -60 mV) were similarly inhibited by mirtazapine in the absence and presence of 100 µM zinc (IC50 ∼15 µM); however, the ACh-induced currents were stronger inhibited with 20 and 50 µM mirtazapine in the presence of zinc. Furthermore, the potentiation of ACh-induced current by zinc in the presence of 5 µM mirtazapine was 1.48 ±â€¯0.06, and with 50 µM mirtazapine zinc potentiation did not occur. Interestingly, in stratum radiatum interneurons (at -70 mV), 20 µM mirtazapine showed less inhibition of the current elicited by choline (Ch) than at 10 µM (0.81 ±â€¯0.02 and 0.74 ±â€¯0.02 of the Ch-induced current, respectively). Finally, the inhibitory effects of mirtazapine depended on membrane potential: 0.81 ±â€¯0.02 and 0.56 ±â€¯0.05 of the control Ch-induced current at -70 and -20 mV, respectively. These results indicate that mirtazapine interacts with muscle and neuronal nAChRs, possibly into the ion channel; that zinc may increase the sensitivity of nAChRs to mirtazapine; and that mirtazapine decreases the sensitivity of nAChRs to zinc.


Assuntos
Potenciais da Membrana/efeitos dos fármacos , Mianserina/análogos & derivados , Receptores Nicotínicos/efeitos dos fármacos , Zinco/farmacologia , Animais , Antidepressivos/farmacologia , Interneurônios/efeitos dos fármacos , Mianserina/farmacologia , Mirtazapina , Neurônios/efeitos dos fármacos , Antagonistas Nicotínicos/farmacologia , Oócitos/efeitos dos fármacos , Ratos Sprague-Dawley
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