Regulatory Peptides, 38 (1992) 1-11

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© 1992 Elsevier Science Publishers B.V. All rights reserved. 0167-0115/92/$05.00

R E G P E P 01144

Review

Signal transduction of Vl-Vascular vasopressin receptors Marc Thibonnier Division of Endocrinology and Hypertension, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH (U.S.A.) (Received 1 October 1991; accepted 31 October 1991)

K e y words." A n t i d i u r e t i c h o r m o n e ;

Second

Membrane

receptor;

I. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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II. Introduction

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Vasoactive

messenger;

hormone

Contents

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III. Radioligands used for characterization of V~-vascular AVP receptors

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IV. Initial binding of AVP to specific membrane V~-vascular receptors . . . . . . A. Surface location of V~-vascular AVP receptors . . . . . . . . . . . . . . B. Lateral mobility of V~-vascular AVP receptors . . . . . . . . . . . . . . C. Internalization of V l-vascular AVP receptors . . . . . . . . . . . . . . .

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V. Immediate transmembrane signaling of V~-vascular AVP receptors . . . . . . . A. V ~-vascular AVP receptors couple to a G-protein . . . . . . . . . . . . . B. V~-vascular AVP receptors' production of inositol phosphates and diacylglycerol via phospholipases C and D . . . . . . . . . . . . . . . . . . . . . . C. Role of phospholipase A 2 . . . . . . . . . . . . . . . . . . . . . . . D. Activation of protein kinase C . . . . . . . . . . . . . . . . . . . . . E. Nature of AVP-induced Ca 2 + transients . . . . . . . . . . . . . . . . . F. Effect of AVP on intracellular pH . . . . . . . . . . . . . . . . . . . . G. Desensitization of V~-vascular AVP receptors . . . . . . . . . . . . . .

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Correspondence." M. Thibonnier, Room W 165, Division of Endocrinology and Hypertension, Department of Medicine, Case Western Reserve University School of Medicine, 10900 Euccid Avenue, Cleveland, OH 44106-4982, U.S.A.

VI. Secondarynuclear signalingof V~-vascularAVP receptors . . . . . . . . . . A. Cellularhypertrophicand hyperplasticactions of AVP . . . . . . . . . . . B. AVP stimulationof protein phosphorylation . . . . . . . . . . . . . . . C. AVP modulationof gene expression . . . . . . . . . . . . . . . . . . .

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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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I. Summary This review covers the recent developments gained in the exploration of Vl-Vascular vasopressin (AVP) receptors. We examine the different radioligands available for the pharmacological characterization of these receptors. The immediate transmembrane signaling of V,-vascular AVP receptors involves ligand-receptor complex formation, receptor lateral mobility and internalization, coupling to a Gq protein, activation of phospholipases A 2, C and D, translocation and activation of protein kinase C, production of inositol 1,4,5-triphosphate and 1,2-diacylglycerol, mobilization of intracellular calcium, alteration of intracellular pH with activation of the Na ÷/H ÷ exchanger, calmodulin activation and myosin light chain phosphorylation. The secondary nuclear signal mechanisms triggered by activation of Vl-vascular AVP receptors includes tyrosine phosphorylation, induction of gene expression and protein synthesis.

II. Introduction Vasopressin (AVP), the antidiuretic hormone plays a major role in the regulation of body fluid volume and osmolality as well as in the maintenance of blood pressure. In addition, AVP exerts a wide array of physiological effects. For instance, AVP stimulates glycogenolysis and neoglucogenesis, corticotropin release, urea reabsorption, platelet aggregation, release of coagulation factors, the firing rate of certain neurons and cell proliferation. All these actions are mediated through activation of specific membranebound receptors present at the surface of the target cells. On the basis of pharmacological and functional studies, Michell et al. proposed in 1979 to distinguish two types of vasopressin (AVP) receptors [ 1]. These authors reported that activation of hepatic AVP receptors led to a rise in cytosolic free calcium and an increase in phosphatidyl-inositol breakdown. They suggested that they be named V1-AVP receptors. By contrast, renal AVP receptors involved in free water reabsorption via activation of adenylate cyclase were labeled V2-AVP receptors. This classification is now widely referred to, usually as Vl-vascular and V2-renal AVP receptors. This nomenclature has been recently amended, as several authors reported that AVP receptors present in the anterior pituitary had a slightly different pharmacological profile in terms of binding characteristics of AVP analogs [2-4]. The term V1 b was proposed by S. Jard et al. to distinguish these receptors from the classical Via-vascular receptors [2]. With the cloning of AVP receptors nearing, the elucidation of their sequences will undoubtedly facilitate and

3 extend the categorization of AVP receptors following the example of the family of ~ and fl adrenergic receptors.

IlL Radioligands used for characterization of Vl-Vascular AVP receptors Tritiated AVP or lysine vasopressin (LVP) were the first radioligands employed to identify V~-vascular AVP receptors in diverse tissues or organs including freshly isolated or cultured arterial smooth muscle cells, immortalized smooth muscle cell lines A~o and A7rs, hepatocytes, human platelets, renal mesangial cells, adrenal glomerulosa cells, reproductive organs, the hippocampus, the rat mammary tumor cell line WRK- 1, human lymphocytes and monocytes. Calculated from saturation and competition experiments, the binding equilibrium dissociation constant (Ko) for tritiated AVP or LVP is in the nanomolar range for in vitro and in vivo preparations. One single class of receptors is present with a maximum number of binding sites varying between tens and hundreds of fmol/mg of protein, depending on the tissue and the extent of purification of the preparation used. Iodinated AVP was seldom used to characterize AVP receptors because of a reduced affinity and a significant amount of non specific binding. Recently, more versatile radioligands were developed to explore V~-vascular AVP receptors. Ligands derived from the first truly potent and specific V~-antagonist (the so-called Manning's compound d[CH 2 ]sTyr[ Me]AVP) were either tritiated or iodinated while retaining a high affinity for the V~-vascular AVP receptors (Table I). Following the discovery by Manning et al. that linear antagonists retained an excellent affinity for AVP receptors [5 ], radioionidated linear Vl-antagonists were prepared. Compound # 6 in our hands [6] and compound # 7 as recently reported by Schmidt et al. [7] display an excellent affinity for V~-vascular AVP receptors. Due to their high specific activity and specificity and low non specific binding, these new linear radioligands can be advantageously used not only for binding studies, but also for autoradiographic and purification purposes. In addition to the radioligands described here, numerous and valuable AVP agonists

TABLE I Different radiolabeled ligands specific for Vt-vascular AVP receptors Radioligand

Kd (nmol)

(1) (2) (3) (4) (5) (6) (7)

0.6-3 0.28-0.30 0.2-0.5 0.28 3.0 0.52 0.06

[3H]AVP [3H)d(CH2)sTyr(Me)AVP [3HIdesGlyd(CH2)5D-Tyr(Et)VAVP [lZSI]d(CH2)sTyr(Me)2Tyr(NHz)9AVP [125I]d(CH2)sSar7AVP [~25I]Phaa-D-Tyr(Et)PheGlnArgProTyr-NH2 [125I]Phaa-o-Tyr(Me)PheGlnAsnArgProArgTyr-NH2

Rat liver, vascular smooth muscle cells and human platelet preparations were used to determine the dissociation constants for these radioligands.

4 and antagonists have been developed by M. Manning and W. Sawyer to study AVP and oxytocin actions as recently reviewed by these authors [5].

IV. Initial binding of AVP to specific membrane Vl-vascular receptors IV-A. Surface location of V~-vascular A VP receptors AVP binds to specific V~-vascular AVP receptors located in the plasma membrane of target tissues. Saturation binding experiments performed with [3H ]AVP and smooth muscle cells in culture revealed up to 110,000 sites per cell during growth and 60,000 sites per cell in stationary culture [ 8 ]. It is worth noting that primary cultures of smooth muscle cells and hepatocytes are associated with both loss and desensitization of AVP receptors after 24 h in culture whereas renal mesangial cells in culture retain their AVP receptors. Using the biotinylated AVP analog d(CH2)sTyr(Me)2Lys(N-biotinamido caproate)NH9AVP, Howl et al. could visualize V~-vascular AVP receptors on the surface of WRK-1 cells and hippocampal neurons, by using streptavidin-gold with electron microscopy and fluorescein-avidin with light microscopy [9]. These gold particles were observed on the external surface of the plasmalemma and were on average 671 + 259 per cell.

IV-B. Lateral mobility of V~-vascular A VP receptors Binding to the membrane receptors is a dynamic phenomenon. Jans et al. used the fluorescent AVP analog 1-deamino[8-1ysine(N6-tetramethylrhodamylaminothio-car bonyl)]AVP and could document lateral mobility of Vrvascular AVP receptors of Avr5 smooth muscle cells in culture [ 10]. This lateral mobility of V~-vascular AVP receptors certainly facilitates their interaction with G-proteins and subsequent internalization and desensitization. The apparent lateral diffusion coefficient D was temperature-dependent, being 5.1 • 10- ~ocm2/s at 37 °C and falling to 2.9.10- ~ocm2/s at 13 °C. These values are higher than that observed for the V2-renal AVP receptors of LLC-PK~ renal epithelial cells. Also, the relatively lower fraction ( f = 0.36 to 0.52) of mobile AVP receptors of A7r5 cells receptors when compared to V2-renal AVP receptors ( f = 0.91) presumably results from the rapid internalization of the former receptors.

IV-C. Internalization of Vl-vascular A VP receptors Fluorescent and biotinylated AVP analogs have been used to demonstrate that AVP receptor-ligand complexes undergo receptor-mediated endocytosis (see Ref. 11 for review). Receptor-mediated endocytosis involves the rapid internalization of the AVP receptor-ligand complexes followed by delivery to the intraceUular endosomes, with subsequent delivery to the lysosomes (the degradative pathway) or plasma membrane (the recycling pathway). Internalization is an energy- and temperature-dependent phenomenon involving actin and tubulin filaments as well as calmodulin and calcium. The internalization pattern of AVP receptors seems to vary with the source and type

of receptors studied. In Alosmooth muscle cells and human platelets, internalized AVP receptors were not returned to the surface whereas they do recycle to the cell surface in A7r 5 smooth muscle cells and hepatocytes [11-13].

V. Immediate transmembrane signaling of Vl-vascular AVP receptors V-A. V~-vascular A VP receptors couple to a G-protein Binding of AVP to its specific V~-vascular AVP receptors is modulated by divalent cations, aluminium fluoride and GTP analogs [9-13]. V~-vascular AVP receptors stimulate GTPase activity and activate phospholipase C in a GTP-dependent manner, suggesting that Vl-vascular AVP receptors are coupled to a guanine nucleotide regulatory protein. Additional evidence indicates that this G-protein is not sensitive to cholera or pertussis toxins. Exton's group recently identified a specific G-protein coupled to rat hepatic Vl-vascular AVP receptors by using specific antibodies directed against the diverse G-ct proteins [ 14]. In liver plasma membranes, two proteins were labeled with a photoreactive GTP analogue in response to incubation with AVP. The labeled proteins have a molecular mass of 42 and 43 kDa. This specific labeling is magnesiumdependent and is attenuated by a specific V~-vascular antagonist. Immunodetection and immunoprecipitation of the labeled proteins with different antibodies raised against Gs, Gi, G z and Gq proteins indicate that these proteins are members of the recently described Gq class of G proteins. V-B. Vl-vascular A VP receptors" production of inositol phosphates and diacylglycerol via phospholipases C and D An early signal linked to the activation of V1-vascular AVP receptors is the hydrolysis of polyphosphoinositides (PIP2) by phospholipase C leading to the production of inositol 1,4,5-triphosphate (IP3) and 1,2-diacylglycerol (DAG) [15,16]. The formation of IP 3 is directly responsible for the initial spike of Ca 2 + mobilization noted in fura-2 loaded smooth muscle cells. The time-course of accumulation of DAG in hepatocytes stimulated with AVP was different from that of IP s. HPLC analysis of DAG in stimulated cells identified two peaks. The fatty acid composition of the later eluting DAG peak was significantly different from PIP 2 and it was suspected that phosphatidylcholine (PC) was the source of production of DAG from nonphosphoinositide sources. In hepatocytes [ 15], A7r5 cells [16] and A~o cells [17], AVP stimulated the production ofphosphatidic acid and DAG from PC as shown by experiments carried out with cells labeled with [3H]glycerol, [3H]myristic acid or [all]choline. The temporal production of phosphatidic acid and DAG as well as the release of choline in the medium were consistent with the activation of phospholipase D by AVP. This was confirmed by the demonstration that AVP stimulated a transphophatidylation reaction which is characteristic of phospholipase D. The relative importance of the different mechanisms involved in PC hydrolysis (protein kinase C, Ca 2+, tyrosine phosphorylation and G-proteins) remains to be demonstrated. The prolonged formation of DAG from PC could be important in cellular events requiring long term activation of protein kinase C.

V-C. Role of phospholipase A: As noted above, the activation of Vl-vascular AVP receptors stimulates the breakdown of PC. The hydrolysis of PC by phospholipase A 2 produces arachidonic acid (AA) which is subsequently metabolized to several eicosanoid metabolites. We have shown that AA potentiates AVP-induced influx of extraceUular Ca 2+ and mobilization of intracellular Ca 2 + in A7r 5 cells [ 16]. Metabolites of the cyclooxygenase pathway are involved, as indomethacin reduces the influx of extracellular Ca 2 + stimulated by AVP. The lipoxygenase pathway is not implicated because lipoxygenase inhibitors do not alter AVP-induced Ca 2+ transients. Interestingly, ketoconazole, an inhibitor ofcytochrome P-450, provoked a dose-dependent reduction of AVP stimulation of Ca 2 ÷ signals. 5,6-Epoxyeicosatrienoic acid potentiated AVP action on Ca 2 + mobilization. Reverse phase H P L C of extracts of [ 14C]AA-loaded Avr 5 cells revealed that AVP potentiated the formation of an epoxy metabolite [ 18]. V-D. Activation of protein kinase C The AVP-induced mobilization of Ca 2 + and production of D A G triggers the activation and translocation of protein kinase C (PKC) from the cytosol to the plasma membrane. This translocation activates PKC which in turn catalyzes several protein phosphorylations implicated in further cell activation and subsequent biological responses. In addition, PKC most likely acts on the coupling between AVP receptors and the G-protein, because phorbol esters (which activate PKC directly) reduce AVPsensitive phospholipase C but do not alter sodium fluoride-sensitive phospholipase C, AVP binding, or inositol lipid pools [ 19]. These observations suggest that PKC may participate in the initial step of homologous desensitization of Vl-Vascular AVP receptors. V-E. Nature of A VP-induced Caz ÷ transients An increase in intracellular free calcium ([Ca 2 + ]i) is the hallmark ofVl-vascular AVP receptor activation. In fura-2 loaded A7r 5 cells, AVP addition results in a biphasic increase in [Ca 2+ ]i composed of a rapid (within 2-5 s) and transient spike, followed by a smaller but steadier increase with return to the basal level 3 to 5 min after addition of AVP [ 16 ]. The preaddition of the V~-antagonist d(CH 2)STyr(Me)AVP blocks AVPinduced increase in [Ca 2 + ]i. The [Ca 2 + ]i response to AVP is concentration dependent with an EDso = 1.87 + 0.15 nM, i.e., close to the K d for the AVP receptors. While the baseline [Ca 2+ ]i level is 136 + 18 nM, the maximal response induced by 1 # M AVP is 1582 + 297 nM. Diverse experiments performed by chelating extracellular Ca 2 + with EDTA or intracellular Ca 2 + with 1,2-bis(O-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethylester, by blocking intracellular Ca 2 + ATPase with terbutylbenzo hydroquinone, or in the presence of the voltage-dependent Ca 2 + channel blocker nifedipine suggest that the initial [Ca 2+ ]~ spike results from both intracellular Ca 2 + release from the endoplasmic reticulum and extracellular Ca 2 + influx, whereas the sustained phase depends on dihydropyridine-insensitive extracellular Ca 2 + influx.

V-F. Effect of A VP on intracellular p H

The massive release of free intracellular C a 2+ induced by the activation of VIvascular AVP receptors results in an early and transient acidification of intracellular pH and a Ca 2 + effiux [20]. The time course and magnitude of the Ca 2 + effiux correlate with the acidification response. The initial acidification response is due to an ATPdependent unidirectional H + influx and is followed by a slower recovery phase involving an amiloride-sensitive Na + influx, presumably via activation of the N a + / H + exchanger. This early acidification and subsequent alkalinization in response to several agonists is now regarded as an important event in excitation-contraction coupling as well as in mitogenic events. V-G. Desensitization of Vl-vascular A VP receptors

Desensitization, i.e., the loss of cellular responsiveness to a hormone after repeated exposure, occurs with AVP in cells expressing specific Vl-vascular AVP receptors. It translates into the reduction of specific binding as well as the decrease of inositol phosphates' production and calcium mobilization. Caramelo et al. [21 ] used [ 3H ]AVP binding, Ca 2 + mobilization and intracellular pH monitoring to explore the desensitization to AVP in smooth muscle cells in culture. AVP desensitization was homologous, concentration-dependent, and occurred within 30 s. This desensitization was related to the uncoupling between the hormone-receptor complexes and the intracellular signal transduction as assessed by Ca 2 + peaks. Receptor occupancy was a critical factor in the maintenance of desensitization, as complete hormone washing by acid glycine buffer restored cell response within 5 min. PKC activation was also involved, as its downregulation inhibited the desensitization phenomenon.

VI. Secondary nuclear signaling of Vl-Vascular AVP receptors V I A . Cellular hypertrophic and hyperplastic actions of A VP

As described above, the activation of Vl-Vascular AVP receptors triggers an immediate cascade of intracytoplasmic signals leading to several events including vascular smooth muscle cell contraction, platelet aggregation and glucose production. In addition, AVP is increasingly recognized as a cellular growth factor implicated in a variety of normal and pathologic biological responses, including embryogenesis, and tissue regeneration or proliferation. In vascular smooth muscle cells in culture, AVP induces cellular hypertrophy, increasing cell protein content by 35~o [22]. The cellular hypertrophy is accompanied by an increase in protein synthesis assessed by [35S]methionine incorporation. Both the cellular hypertrophy and the increase in [ 3sS ]methionine incorporation are prevented by a specific V~-vascular antagonist. Moreover, AVP is mitogenic for mouse 3T3 cells, rat adrenal glomerulosa cells, renal mesangial cells and can potentiate hepatocyte regeneration after partial hepatectomy [22]. The signals controlling DNA replication and differential gene expression must be

transduced from the cell surface to the nucleus. Despite the large knowledge of the early consequences of AVP binding to its plasma membrane V~-vascular receptors in terms of second messengers and activation of protein kinase, there is little information on the actual mechanisms involved in the transmission of AVP signals from the cytoplasm to the nucleus. Protein phosphorylation-dephosphorylation reactions play a pivotal role in amplifying and diffusing incoming signals throughout the cells.

VI-B. A VP stimulation o]'protein phosphorylation In the model of human platelets, we found that in the presence of extracellular C a 2 +, AVP provoked the phosphorylation of two substrates of M r 45,000 and 22,000 [23]. This phosphorylation pattern was similar to that observed with thrombin and involved the activation of protein kinase C and calcium-calmodulin kinase. Tyrosine phosphorylation is an important element in the signal transduction of mitogenis agents like platelet-derived growth factor (PDGF). Until recently, it was not known whether tyrosine phosphorylation played a role in the mitogenic action of G-protein transducing peptides. In quiescent Swiss 3T3 fibroblasts, Zachary et al. recently reported that AVP markedly increases tyrosine and serine phosphorylation of several substrates, including two major bands of M r 90,000 and 115,000 [24]. The phosphorylating effect is rapid, concentration dependent and inhibited by a specific Vl-vascular antagonist. The phosphorylated substrates are not related to previously identified tyrosine kinase substrates (for instance, known targets for the P D G F receptor) and may represent additional targets for peptide-stimulated tyrosine/serine kinase(s). It is likely that tyrosine phosphorylation plays a role in the transduction of the mitogenic response to AVP. It has been postulated that protein phosphorylation may represent a major mechanism controlling nuclear activities such as gene transcription [25]. Translocation of protein kinase C to the nucleus and phosphorylation of transacting factors may be instrumental in signal transduction mechanisms [26].

VI-C. A VP modulation of gene expression The mitogenic effect of AVP implies that AVP differentially regulates gene expression. Very little is known about the pathways by which AVP activates gene expression. The induction of transcription regulatory proteins is a mechanism which has been proposed to link hormone-receptor coupling with long term trophic effects. The synthesis of nuclear protooncogene products Fos, Jun and related proteins is an immediate-early response to a large variety of hormones and growth factors [25]. Some of these proteins interact at their leucine zipper regions to form homo- and heterodimers which bind to a specific DNA sequence, the AP- 1 site present in the 5' regulatory region of many genes including c-fos, c-jun and C-myc. The mitogenic effect of AVP in rat renal mesangial cells is associated with an increase in mRNA levels of the immediate-early response genes, egr-1 and c-fos [27]. The AVP-induced increase in mRNA levels is markedly reduced by cytochrome P-450 inhibitors whereas the cytochrome P-450 metabolite 14,15-epoxyeicosatrienoic acid potentiates the effect of AVP to enhance [3H]thymidine incorporation. Similarly, we

pH a l i l l

Cell Contraction

J

Fig. 1. Immediate and secondary signals activated by V~-vascularAVP receptors. PLC = phospholipaseC, PLD = phospholipase D, PLA2 = phospholipase A2, PA = phosphatidic acid, AA = arachidonic acid, PC = phosphatidylcholine, PKC = protein kinase C, ER = endoplasmic reticulum, CO ; cyclooxygenase pathway, EPO = epoxygenase pathway, IP3 = 1,4,5-inositol triphosphate, DAG= 1,2-diacylglycerol, Gq = G-protein.

found that in A7r 5 smooth muscle cells, AVP produced a time-dependent increase in c-los and c-jun m R N A s without altering the level of expression of G A P D H m R N A which was constitutively expressed in these cells [ 18]. These initial data suggest that the Fos and Jun families of regulatory proteins could play a role in mediating long term trophic responses of cells exposed to AVP. In conclusion, the present minireview demonstrates that AVP is involved in diverse cellular events through activation of specific membrane-bound Vl-Vascular receptors triggering numerous immediate cytoplasmic and secondary nuclear signals. The presently known short-term and long-term signal transduction ofAVP V 1-vascular receptors is depicted on Fig. 1. The imminent cloning and purification of Vl-Vascular AVP receptors as well as the further elucidation of nuclear signals triggered by AVP will undoubtedly facilitate our understanding of the physiology and pathophysiology of AVP and presumably lead to useful therapeutic interventions in human diseases.

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References 1 Michell, R.H., Kirk, J.C. and Billah, M.M., Hormonal stimulation of phosphatidylinositol breakdown with particular reference to the hepatic effects of vasopressin, Biochem. Soc. Trans., 7 (1979) 861-865. 2 Jard, S., Gaillard, R. C., Guillon, G., Marie, Schoenenberg, P., Muller, A. F., Manning, M. and Sawyer, W. H., Vasopressin antagonists allow demonstration of a novel type of vasopressin receptor in the rat adenohypophysis, Mol. Pharmacol., 30 (1986) 171-177. 3 Knepel, W., G6tz, D. and Fahrenholz, F., Interaction of rat adenohypophyseal vasopressin receptors with vasopressin analogues substituted at positions 7 and 1: dissimilarity from the V~ vasopressin receptor, Neuroendocrinology, 44 (1986) 390-396. 4 Schwartz, J., Derdowska, I., Sobocinska, M. and Kupryszeswki, G., A potent new synthetic analog of vasopressin with relative agonist specificity for the pituitary, Endocrinology, 129 (1991) 1107-1109. 5 Manning, M. and Sawyer, W. H., Discovery, development, and some uses ofvasopressin and oxytocin antagonists, J. Lab. Clin. Med., 114 (1989) 617-632. 6 Thibonnier, M. and Bayer, A.L., Rapid purification ofV 1 vasopressin receptors of human platelets with biotinylated and radioiodinated linear antagonists, Abstract No. 709, The Endocrine Society, 1991 Meeting. 7 Schmidt, A., Audigier, S., Barberis, C., Jard, S., Manning, M., Kolodziejczyk, A. S. and Sawyer, W. H., A radioiodinated linear vasopressin antagonist: a ligand with high affinity and specificity for Via receptors, FEBS Lett., 282 (1991) 77-81. 8 Howl, J., Kerr, I. D., Chan, C. H. W. and Wheatley, M., A selective biotinylated probe for Via vasopressin receptors, Mol. Cell. Endocrinol. 77 (1991) 123-131. 9 Stassen, F.L., Heckman, G., Schmidt, D., Aiyar, N., Nambi, P. and Crooke, S.T., Identification and characterization of vascular (V~) vasopressin of an established smooth muscle cell line, Mol. Pharmacol., 31 (1987) 259-266. 10 Lutz, W., Salisbury, J. L. and Kumar, R., Vasopressin receptor-mediated endocytosis: current view, Am. J. Physiol., 261 (1991) F1-F13. 11 Jans, D.A., Peters, R. and Fahrenholz, F., Lateral mobility of the phospholipase C-activating vasopressin V~-type receptor in ATr5 smooth muscle cells: a comparison with the adenylate cyclase-coupled V2-receptor, EMBO J., 9 (1990) 2693-2699. 12 Fishman, J.B., Dickey, B.F., Bucher, N.L.R. and Fine, R.E., Internalization, recycling, and redistribution of vasopressin receptors in rat hepatocytes, J. Biol. Chem., 260 (1985) 12641-12546. 13 Thibonnier, M., Vasopressin agonists and antagonists, Horm. Res., 34 (1990) 124-128. 14 Wange, R.L., Smrcka, A.V., Sternweis, P.C. and Exton, J.H., Photoaffinity labeling of two rat liver plasma membrane proteins with [32p]gamma-azidoanilido GTP in response to vasopressin, J. Biol. Chem., 266 (1991) 11409-11412. 15 Extort, J.H., Signaling through phosphatidylcholine breakdown, J. Biol. Chem., 265 (1990) 1-4. 16 Thibonnier, M., Bayer, A.L., Simonson, M.S. and Kester, M., Multiple signaling pathways of V~vascular AVP receptors of ATr~ cells, Endocrinology, 129 (1991) 2845-2856. 17 Welsh, C., Scheichel, K., Cao, H. and Chabbott, H., Vasopressin stimulates phospholipase D activity against phosphatidytcholine in vascular smooth muscle ceils, Lipids, 25 (1990) 675-684. 18 Thibonnier, M., Bayer, A. L., Simonson, M. S. and Koop, D. R., V ~-vascular AVP receptors OfATr5 cells activate the arachidonic acid cyclooxygenase and epoxygenase pathways, J. Am. Soc. Nephrol., 2 (1991 ) 432, abstract. 19 Gallo-Payet, N., Chouinard, L., Balestre, M.N. and Guillon, G., Involvement of protein kinase C in the coupling between the V~-vasopressin receptor and phospholipase C in rat glomerulosa cells: effects on aldosterone secretion, Endocrinology, 129 (1991) 623-634. 20 Berk, B.C., Brock, T.A., Gimbrone, M.A. and Alexander, R.W., Early agonist-mediated ionic events in cultured vascular smooth muscle cells, J. Biol. Chem., 262 (1987) 5065-5072. 21 Caramelo, C., Tsai, P., Okada, K., Briner, V.A. and Schrier, R.W., Mechanisms of rapid desensitization to arginine vasopressin in vascular smooth muscle cells, Am. J. Physiol., 260 (1991) F46-F52. 22 Geisterfer, A. A. F. and Owens, G. K., Arginine-vasopressin-induced hypertrophy of cultured rat aortic smooth muscle cells, Hypertension, 14 (1989) 413-420.

11 23 Thibonnier, M., Hinko, A. and Pearlmutter, A.F., The human platelet vasopressin receptor and its intracellular messengers: key role of divalent cations, J. Cardiovasc. Pharmacol., 10 (1987) 24-29. 24 Zachary, I., Gil, J., Lehmann, W., Sinnett-Smith, J. and Rozengurt, E., Bombesin, vasopressin, and endothelin rapidly stimulate tyrosine phosphorylation in intact Swiss 3T3 cells, Proc. Natl. Acad. Sci. USA., 88 (1991) 4577-4581. 25 Nigg, E. A., Mechanisms of signal transduction to the cell nucleus, Adv. Cancer Res., 55 (1990) 271-311. 26 Hocevar, B. A. and Fields, A., Selective translocation ofbetalI-protein kinase C to the nucleus of human promyelocytic (HL60) leukemia cells, J. Biol. Chem., 266 (1991) 28-33. 27 Sellmayer, A., Uedelhoven, W. M., Weber, P.C. and Bonventre, J.V., Endogenous non-cyclooxygenase metabolites of arachidonic acid modulate growth and mRNA levels of immediate-early response genes in rat mesangial cells, J. Biol. Chem., 266 (1991) 3800-3807.

Signal transduction of V1-vascular vasopressin receptors.

This review covers the recent developments gained in the exploration of V1-vascular vasopressin (AVP) receptors. We examine the different radioligands...
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