Multiple α₁-adrenergic receptor subtypes support synergistic stimulation of vasopressin and oxytocin release by ATP and phenylephrine

Abstract

Simultaneous exposure of explants of the hypothalamo-neurohypophyseal system (HNS) to ATP and the α(1)-adrenergic receptor (α(1)-R) agonist, phenylephrine (ATP+PE) induces a synergistic stimulation of vasopressin and oxytocin (VP/OT) release that is sustained for hours. The current studies confirm that the synergism is dependent upon activation of α(1)-R by demonstrating that an α(1)-R antagonist prevents the response. The role of the α(1)A, B, and D-adrenergic receptor subtypes in the synergistic effect of ATP+PE on intracellular calcium ([Ca(2+)](i)) in supraoptic nucleus (SON) neurons and VP/OT release from neural lobe was evaluated. The increase in [Ca(2+)](i) induced by PE in SON predominantly reflects release from intracellular stores and is mediated by activation of the α(1)A adrenergic receptor subtype. The α(1)A subtype is also required for the sustained elevation in [Ca(2+)](i) induced by ATP+PE. In contrast, although synergistic stimulation of VP/OT release was eliminated by removal of PE and was blunted by benoxathian, an α(1)-R antagonist that is not subtype selective, no single α(1)-R subtype selective antagonist prevented sustained stimulation of VP/OT release by ATP+PE. Thus, sustained activation of α(1)-R is essential for the synergistic VP and OT response to ATP+PE, but multiple α(1)-R subtypes can support the response. Redundancy amongst the α(1)-R subunits in supporting this response is consistent with the predicted importance of the response for sustaining the elevated VP release required to prevent cardiovascular collapse during hemorrhage and sepsis.

Activation of alpha‐1 adrenergic receptors increases cytosolic calcium in neurones of the paraventricular nucleus of the hypothalamus

“…The SON, a similar hypothalamic nucleus innervated by adrenergic projections from the nTS and VLM, has similar α 1 ‐AR mediated excitation. Specifically, NE increased SON excitability via an α 1 ‐AR mediated increase in burst firing, and α 1 ‐AR activation also increases [Ca 2+ ] i in the SON similar to results seen in the PVN. However, NE has also been observed to decrease excitability in the SON as well .…”

“…Outside of the effect of NE on synaptic transmission to parvocellular and magnocellular neurones, less is known regarding what other functions NE has in the PVN. In other hypothalamic nuclei, including the supraoptic nucleus (SON), NE increases intracellular Ca 2+ ([Ca 2+ ] i ) via α 1 ‐AR mediated pathways . In the nTS, α 1 ‐AR activation induces neuronal [Ca 2+ ] i oscillations and increased excitation .…”

“…In other hypothalamic nuclei, including the supraoptic nucleus (SON), NE increases intracellular Ca 2+ ([Ca 2+ ] i ) via α 1 -AR mediated pathways. [35][36][37][38] In the nTS, α 1 -AR activation induces neuronal [Ca 2+ ] i oscillations and increased excitation. 39 Given the presence of ARs in the PVN, 17,18,40 catecholaminergic nTS neurones that innervate the PVN 11,12 and the importance of [Ca 2+ ] i on cellular function, including neurotransmitter release, membrane potential, and gene and protein function, 41 we examined the influence and mechanism by which NE modulates [Ca 2+ ] i in PVN neurones.…”

Purinergic signalling in endocrine organs

“…In keeping with the features of cotransmission, ATP (via P2X receptors) and phenylephrine (via α 1 adrenoceptors) act synergistically to stimulate AVP release [487,497,500]. Synergistic activation of astrocytes by ATP and NA in the rat supraoptic nucleus has also been described ([143]; Fig.…”

Purinergic signaling pathways in endocrine system

“…Each of these transmitters causes a small and transient amplitude response, whereas their coapplication causes a larger and sustained response in hormone secretion. This synergism appears to involve receptors on the perikaryon of VP and OT neurons, including several subtypes of P2XRs and α1 adrenergic receptors (Gomes et al, 2009; Sladek et al, 2008; Song et al, 2010). Others also indicated the expression of multiple P2XRs in SON neuronal bodies and described their activation induced rise in intracellular calcium concentration ([Ca 2+ ] i ) (Shibuya et al, 1999).…”