Purinergic P2 and glutamate NMDA receptor coupling contributes to osmotically driven excitability in hypothalamic magnocellular neurosecretory neurons

Autor(es)

Ferreira-Neto, H. C. ^{[1, 2]} ; Antunes, V. R. ^[3] ; Stern, J. E. ^[2]

Afiliação do(s) autor(es)

^[1] Georgia State Univ, Atlanta, GA 30303 - USA

^[2] Georgia State Univ, Neurosci Inst, 100 Piedmont Ave SE, Atlanta, GA 30303 - USA

^[3] Univ Sao Paulo, Inst Biomed Sci, Dept Physiol & Biophys, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF PHYSIOLOGY-LONDON; v. 599, n. 14, p. 3531-3547, JUL 2021.
• Citações Web of Science: 0

Resumo

Key points Purinergic and glutamatergic signalling pathways play a key role in regulating the activity of hypothalamic magnocellular neurosecretory neurons (MNNs). However, the precise cellular mechanisms by which ATP and glutamate act in concert to regulate osmotically driven MNN neuronal excitability remains unknown. Here, we report that ATP acts on purinergic P2 receptors in MNNs to potentiate in a Ca2+-dependent manner extrasynaptic NMDAR function. The P2-NMDAR coupling is engaged in response to an acute hyperosmotic stimulation, contributing to osmotically driven firing activity in MNNs. These results help us to better understand the precise mechanisms contributing to the osmotic regulation of firing activity and hormone release from MNNs. The firing activity of hypothalamic magnocellular neurosecretory neurons (MNNs) located in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) is coordinated by the combined, fine-tuned action of intrinsic membrane properties, synaptic and extrasynaptic signalling. Among these, purinergic and glutamatergic signalling pathways have been shown to play a key role regulating the activity of MNNs. However, the precise cellular mechanisms by which ATP and glutamate act in concert to regulate osmotically driven MNN neuronal excitability remains unknown. Whole-cell patch-clamp recordings obtained from MNNs showed that ATP (100 mu M) induced an increase in firing rate, an effect that was blocked by either 4-{[}{[}4-formyl-5-hydroxy-6-methyl-3-{[}(phosphonooxy)methyl]2-pyridiny l]azo]1,3-benzenedisulfonic acid tetrasodium salt (PPADS) (10 mu M) or kynurenic acid (1 mm). While ATP did not affect the frequency or magnitude of glutamatergic excitatory postsynaptic currents (EPSCs), it induced an inward shift in the holding current that was prevented by PPADS or kynurenic acid treatment, suggesting that ATP enhances a tonic extrasynaptic glutamatergic excitatory current. We observed that ATP-potentiated glutamatergic receptor-mediated currents were evoked by focal application of L-glu (1 mm) and NMDA (50 mu M), but not AMPA (50 mu M). ATP potentiation of NMDA-evoked currents was blocked by PPADS (10 mu M) and by chelation of intracellular Ca2+ with BAPTA (10 mm). Finally, we report that a hyperosmotic stimulus (mannitol 1%, +55 mOsm/kgH(2)O) potentiated NMDA-evoked currents and increased MNN firing activity, effects that were blocked by PPADS. Taken together, our data support a functional excitatory coupling between P2 and extrasynaptic NMDA receptors in MNNs, which is engaged in response to an acute hyperosmotic stimulus. (AU)

• Processo FAPESP: 10/17997-0 - Mecanismos da neurotransmissão purinérgica do hipotálamo sobre a atividade autonômica simpática e sua relação com a hipertensão neurogênica
• Beneficiário: Vagner Roberto Antunes
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 12/12444-8 - Estudo dos mecanismos de modulação sináptica e interação neurônio-glia de receptores purinérgicos e glutamatérgicos em neurônios autônomos do núcleo paraventricular do hipotálamo
• Beneficiário: Hildebrando Candido Ferreira Neto
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado
• Processo FAPESP: 10/05037-1 - Papel dos receptores purinérgicos do núcleo paraventricular do hipotálamo na hipertensão neurogênica
• Beneficiário: Hildebrando Candido Ferreira Neto
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 16/21991-3 - Hipertensão secundária à alta ingestão de sal: estudo da sinalização purinérgica em células neuronais do hipotálamo e sua influência na atividade do sistema nervoso autônomo e pressão arterial
• Beneficiário: Vagner Roberto Antunes
• Modalidade de apoio: Auxílio à Pesquisa - Regular