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NEUROHUMORAL CONTROL OF CARDIOVASCULAR FUNCTION

ATP increases intracellular calcium in supraoptic neurons by activation of both P2X and P2Y purinergic receptors

Department of Physiology and Biophysics, University of Colorado at Denver and Health Sciences Center, Aurora, Colorado

Submitted 13 July 2006 ; accepted in final form 13 September 2006

ATP increases intracellular calcium concentration ([Ca²⁺]_i) in supraoptic nucleus (SON) neurons in hypothalamo-neurohypophyseal system explants loaded with the Ca²⁺-sensitive dye, fura 2-AM. Involvement of P2X purinergic receptors (P2XR) in this response was anticipated, because ATP stimulation of vasopressin release from hypothalamo-neurohypophyseal system explants required activation of P2XRs, and activation of P2XRs induced an increase in [Ca²⁺]_i in dissociated SON neurons. However, the ATP-induced increase in [Ca²⁺]_i persisted after removal of Ca²⁺ from the perifusate ([Ca²⁺]_o). This suggested involvement of P2Y purinergic receptors (P2YR), because P2YRs induce Ca²⁺ release from intracellular stores, whereas P2XRs are Ca²⁺-permeable ion channels. Depletion of [Ca²⁺]_i stores with thapsigargin (TG) prevented the ATP-induced increase in [Ca²⁺]_i in zero, but not in 2 mM [Ca²⁺]_o, indicating that both Ca²⁺ influx and release of intracellular Ca²⁺ contribute to the ATP response. Ca²⁺ influx was partially blocked by cadmium, indicating a contribution of voltage-gated Ca²⁺ channels. PPADS (pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid), and iso-PPADS, P2XR antagonists, attenuated, but did not abolish, the ATP-induced increase in [Ca²⁺]_i. Combined treatment with PPADS or iso-PPADS and TG prevented the response. A cocktail of P2YR agonists consisting of UTP, UDP, and 2-methylthio-ADP increased [Ca²⁺]_i (with or without tetrodotoxin) that was markedly attenuated by TG. 2-Methylthio-ADP alone induced consistent and larger increases in [Ca²⁺]_i than UTP or UDP. MRS2179, a specific P2Y₁R antagonist, eliminated the response to ATP in zero [Ca²⁺]_o. Thus, both P2XR and P2YR participate in the ATP-induced increase in [Ca²⁺]_i, and the P2Y₁R subtype is more prominent than P2Y₂R, P2Y₄R, or P2Y₆R in SON.

calcium imaging; fura-2 acetoxymethyl ester; thapsigargin; pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid; cadmium

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