TLQP-21 (TLQPPASSRRRHFHHALPPAR) is a multifunctional peptide that is involved in the control of physiological functions, including feeding, reproduction, stress responsiveness, and general homeostasis. Despite the huge interest in TLQP-21 biological activity, very little is known about its intracellular mechanisms of action. In microglial cells, TLQP-21 stimulates increases of intracellular Ca(2+) that may activate functions, including proliferation, migration, phagocytosis and production of inflammatory molecules. Our aim was to investigate whether JMV5656 (RRRHFHHALPPAR), a novel short analogue of TLQP-21, stimulates intracellular Ca(2+) in the N9 microglia cells, and whether this Ca(2+) elevation is coupled with the activation Ca(2+)-sensitive K(+) channels. TLQP-21 and JMV5656 induced a sharp, dose-dependent increment in intracellular calcium. In 77% of cells, JMV5656 also caused an increase in the total outward currents, which was blunted by TEA (tetraethyl ammonium chloride), a non-selective blocker of voltage-dependent and Ca(2+)-activated potassium (K(+)) channels. Moreover, the effects of ion channel blockers charybdotoxin and iberiotoxin, suggested that multiple calcium-activated K(+) channel types drove the outward current stimulated by JMV5656. Additionally, inhibition of JMV5656-stimulated outward currents by NS6180 (4-[[3-(trifluoromethyl)phenyl]methyl]-2H-1,4 benzothiazin-3(4H)-one) and TRAM-34 (triarylmethane-34), indicated that KCa3.1 channels are involved in this JMV5656 mechanisms of action. In summary, we demonstrate that, in N9 microglia cells, the interaction of JMV5656 with the TLQP-21 receptors induced an increase in intracellular Ca(2+), and, following extracellular Ca(2+) entry, the opening of KCa3.1 channels.

Rivolta, I., Binda, A., Molteni, L., Rizzi, L., Bresciani, E., Possenti, R., et al. (2017). JMV5656, a novel derivative of TLQP-21, triggers the activation of a calcium-dependent potassium outward current in microglial cells. FRONTIERS IN CELLULAR NEUROSCIENCE, 11, 41 [10.3389/fncel.2017.00041].

JMV5656, a novel derivative of TLQP-21, triggers the activation of a calcium-dependent potassium outward current in microglial cells

POSSENTI, ROBERTA;
2017-01-01

Abstract

TLQP-21 (TLQPPASSRRRHFHHALPPAR) is a multifunctional peptide that is involved in the control of physiological functions, including feeding, reproduction, stress responsiveness, and general homeostasis. Despite the huge interest in TLQP-21 biological activity, very little is known about its intracellular mechanisms of action. In microglial cells, TLQP-21 stimulates increases of intracellular Ca(2+) that may activate functions, including proliferation, migration, phagocytosis and production of inflammatory molecules. Our aim was to investigate whether JMV5656 (RRRHFHHALPPAR), a novel short analogue of TLQP-21, stimulates intracellular Ca(2+) in the N9 microglia cells, and whether this Ca(2+) elevation is coupled with the activation Ca(2+)-sensitive K(+) channels. TLQP-21 and JMV5656 induced a sharp, dose-dependent increment in intracellular calcium. In 77% of cells, JMV5656 also caused an increase in the total outward currents, which was blunted by TEA (tetraethyl ammonium chloride), a non-selective blocker of voltage-dependent and Ca(2+)-activated potassium (K(+)) channels. Moreover, the effects of ion channel blockers charybdotoxin and iberiotoxin, suggested that multiple calcium-activated K(+) channel types drove the outward current stimulated by JMV5656. Additionally, inhibition of JMV5656-stimulated outward currents by NS6180 (4-[[3-(trifluoromethyl)phenyl]methyl]-2H-1,4 benzothiazin-3(4H)-one) and TRAM-34 (triarylmethane-34), indicated that KCa3.1 channels are involved in this JMV5656 mechanisms of action. In summary, we demonstrate that, in N9 microglia cells, the interaction of JMV5656 with the TLQP-21 receptors induced an increase in intracellular Ca(2+), and, following extracellular Ca(2+) entry, the opening of KCa3.1 channels.
2017
Pubblicato
Rilevanza internazionale
Articolo
Esperti non anonimi
Settore BIO/14 - FARMACOLOGIA
Settore BIO/09 - FISIOLOGIA
English
Con Impact Factor ISI
Ca2+-activated K+ channels; K+ current; TLQP-21; microglia; patch clamp
Rivolta, I., Binda, A., Molteni, L., Rizzi, L., Bresciani, E., Possenti, R., et al. (2017). JMV5656, a novel derivative of TLQP-21, triggers the activation of a calcium-dependent potassium outward current in microglial cells. FRONTIERS IN CELLULAR NEUROSCIENCE, 11, 41 [10.3389/fncel.2017.00041].
Rivolta, I; Binda, A; Molteni, L; Rizzi, L; Bresciani, E; Possenti, R; Fehrentz, J; Verdie, P; Martinez, J; Omeljaniuk, R; Locatelli, V; Torsello, A...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/185015
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