ATP stimulates rat hypothalamic sympathetic neurons by enhancing AMPA receptor-mediated currents

Abstract

Ferreira-Neto HC, Antunes VR, Stern JE. ATP stimulates rat hypothalamic sympathetic neurons by enhancing AMPA receptormediated currents. J Neurophysiol 114: 159 -169, 2015. First published April 22, 2015 doi:10.1152/jn.01011.2014.-We have previously shown that ATP within the paraventricular nucleus (PVN) induces an increase in sympathetic activity, an effect attenuated by the antagonism of P2 and/or glutamatergic receptors. Here, we evaluated precise cellular mechanisms underlying the ATP-glutamate interaction in the PVN and assessed whether this receptor coupling contributed to osmotically driven sympathetic PVN neuronal activity. Whole-cell patch-clamp recordings obtained from PVN-rostral ventrolateral medulla neurons showed that ATP (100 M, 1 min, bath applied) induced an increase in firing rate (89%), an effect blocked by kynurenic acid (1 mM) or 4-[[4-Formyl-5-hydroxy-6-methyl-3-[(phosphonooxy)methyl]-2-pyridinyl]azo]-1,3-benzenedisulfonic acid tetrasodium salt (PPADS) (10 M). Whereas ATP did not affect glutamate synaptic function, ␣-amino-3-hydroxy-5-methylisoxazole propionic acid (AMPA) receptor-mediated currents evoked by focal application of AMPA (50 M, n ϭ 13) were increased in magnitude by ATP (AMPA amplitude: 33%, AMPA area: 52%). ATP potentiation of AMPA currents was blocked by PPADS (n ϭ 12) and by chelation of intracellular Ca 2ϩ (BAPTA, n ϭ 10). Finally, a hyperosmotic stimulus (mannitol 1%, ϩ55 mosM, n ϭ 8) potentiated evoked AMPA currents (53%), an effect blocked by PPADS (n ϭ 6). Taken together, our data support a functional stimulatory coupling between P2 and AMPA receptors (likely of extrasynaptic location) in PVN sympathetic neurons, which is engaged in response to an acute hyperosmotic stimulus, which might contribute in turn to osmotically driven sympathoexcitatory responses by the PVN.ATP; ␣-amino-3-hydroxy-5-methylisoxazole propionic acid; paraventricular nucleus; rostral ventrolateral medulla; hyperosmolarity BODY FLUID HOMEOSTASIS is tightly regulated by the integration of renal, cardiovascular, and neuroendocrine systems (Share and Claybaugh 1972). An increase in plasma osmolality induces several responses including an increase in sympathetic activity, blood pressure elevation, and the release of neurohormones, such as vasopressin and angiotensin II (Bealer 2000;Hatzinikolaou et al. 1980Hatzinikolaou et al. , 1981Stocker and Toney 2005;Weiss et al. 1996). Part of these responses are mediated through activation of the hypothalamic paraventricular nucleus (PVN) driven by the circumventricular organs in which central osmoreceptors are located (Antunes-Rodrigues et al. 2004;Stocker et al. 2008). The PVN is composed of magnocellular and parvocellular neurons. Magnocellular neurons synthesize and release vasopressin and oxytocin systemically from the posterior pituitary, whereas parvocellular neurons project to premotor sympathoexcitatory neurons located either in the rostral ventrolateral medulla (RVLM) and/or intermediolateral cell column of the spinal cord.Several neurotransmitters in t...

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