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Multiple Signaling Pathways of V₁-Vascular Vasopressin Receptors of A₇5_r Cells^*

Department of Medicine, University Hospitals of Cleveland and Case Western Reserve University School of Medicine Cleveland, Ohio 44106–4982

Address all correspondence and requests for reprints to: Dr. Marc Thibonnier, Division of Endocrinology and Hypertension, Department of Medicine, Case Western Reserve University School of Medicine, 2109 Aldelbert Road, Cleveland, Ohio 44106–4982.

Abstract

We explored the nature and time course of the multiple signal transduction pathways for V₁vascular vasopressin (AVP) receptors of A₇r₆ aortic smooth muscle cells in culture by using radioligand binding techniques, intracellular calcium monitoring, and polyphosphoinositide and phospholipid analyses.

V₁-vascular AVP receptors of A₇r₅ cells were characterized by the agonist radioligand [³H]AVP and the antagonist radioligand [³H]d(CH₂)₅Tyr(Me)AVP. Affinity and capacity of agonist but not antagonist binding were modulated by MgCl₂ and aluminum fluoride, suggesting that the receptors are coupled to a guanine nucleotide regulatory protein.

In fura-2-loaded A₇r₅ cells, AVP induced within seconds a dose-dependent increase of free intracellular Ca⁺⁺ ([Ca⁺⁺]_i) consisting of a rapid transient spike and a sustained increase lasting for 3–5 min. The baseline [Ca⁺⁺]_i was 136 ± 18 nM, the maximum [Ca⁺⁺]_i response to AVP was 1,582 ± 297 nM, and AVP ED₅₀ was 1.87 ± 0.15 nM. Diverse experiments performed with EGTA, 1,2-bis(O-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethylester, Mn⁺⁺, ionomycin, terbutylbenzo hydroquinone, and nicardipine suggested that the initial spike resulted from both intracellular Ca⁺⁺ release from the endoplasmic reticulum and extracellular Ca⁺⁺ influx, whereas the sustained phase depended on dihydropyridine-insensitive extracellular Ca⁺⁺ influx. Experiments done with indomethacin and arachidonic acid indicated that AVP-induced extracellular Ca⁺⁺ influx was in part dependent on phospholipase A₂ activation.

In [³H]myoinositol and [³H]arachidonate-labeled A₇r₆ cells, AVP stimulated inositol 1,4,5 trisphosphate and 1,2 diacylglycerol production via activation of phospholipase C. Also, AVP stimulated a transphosphatidylation reaction through activation of phospholipase D in A₇r₅ cells labeled with [³H]1-O-alkyl lysoglycerophosphocholine.

Thus, the stimulation of V₁-vascular AVP receptors of A₇r₆ cells triggers several signaling pathways. The immediate and transient [Ca⁺⁺]_i rise due to mobilization of intracellular and extracellular Ca⁺⁺ is associated with the activation of phospholipases A₂ and C, and the sustained activation of phospholipase D. (Endocrinology 129: 2845–2856, 1991)

Footnotes

^* This work was supported by NIH Grants R01-HL-39757, P01-HL-41618, and R29-AR-40225.

Received July 5, 1991.

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