^ATP-Mg2+ cAMPf

PK-A activity t

Response in kidney tubule

FIGURE 4-16 Vasopressin receptor (V2 receptor) in the kidney. Abbreviations: G„ stimulatory G protein; AC, adenylate cyclase; cAMP, cyclic AMP, PKA, protein kinase A. Drawing reproduced from "Hormones" (E.-E. Baulieu and P.A. Kelly, eds.), p. 288. Chapman and Hall, New York (1990).

phenylephrine (see Chapter 11), via an increase in cytoplasmic Ca2+, releases glucose from the liver while promoting the uptake of K+. Release of glucose is accomplished by stimulating the breakdown of glycogen. These actions of VP can be blocked by phentolamine, an a-blocking agent whose structure is shown in Figure 4-17.

Glycogenolysis is stimulated by VP in liver by mobilizing intracellular stores of Ca2+ (mitochondria and/ or endoplasmic reticulum), which results in an increase in cytosolic Ca2+. Increased cytosolic Ca2+ stimulates phosphorylase b kinase and, hence, phosphorylase activation (conversion of phosphorylase b to a), extrusion of Ca2+, and uptake of K+. VP interacts with a receptor in the hepatocyte cell membrane, resulting in the generation of a second messenger causing Ca2+ mobilization. Ca2+ released from the intracellular storage sites (e.g., mitochondrion) is expelled from the cell in part by a specific mechanism in the cell membrane. VP also stimulates the phosphorylation of about a dozen proteins in hepatocyte cytosol, including pyruvate kinase

FIGURE 4-17 Structure of phentolamine, an a-blocking agent.

in addition to phosphorylase. Cyclic AMP, a second messenger in ¡6-receptor reactions, is not involved in the effects of VP. VP appears to stimulate the turnover of phosphatidylinositol in hepatocytes, and this effect is linked to either the VP-receptor interaction or the process of extrusion of intracellular Ca2+ and uptake of extracellular Ca2+. A model for the Vj vascular vasopressin receptor action is shown in Figure 4-18. The hepatocyte receptor falls within this general class (see Table 4-1).

F. VP and ACTH Release

It has been known for some time that VP injected at a point where it could gain access rapidly to the hypothalamic-pituitary axis could stimulate the release of ACTH, and indeed, VP is a releasing factor for ACTH in addition to the ACTH-releasing action of CRH (see Chapters 3 and 10). The most likely biological role for VP in this context is to function to potentiate the release of ACTH by CRH, although VP can release some ACTH by itself. CRH has been shown to produce rapid stimulation of cyclic AMP in rat anterior pituitary cells. Although VP agonists cause an increase in CRH-induced ACTH release from rat anterior pituitary cells in culture, VP alone has no effect on cyclic AMP levels in these cells. Its action is mediated by the VP Vlb receptor through the Gpk: protein and is similar to the sequence of events in whole or in part shown in Figure 4-18. However, when combined with CRH, VP causes a twofold increase in the CRH-induced accumulation of cyclic AMP; thus, VP acts by enhancing the effectiveness of CRH. Table 4-1 shows a classification of these receptors.

In addition to its activity in stimulating the direct and indirect (via CRH) release of ACTH from the anterior pituitary, evidence suggests that VP may stimulate Cortisol secretion in the nanomolar range directly from the adrenal cortex through the activation of Vi receptors (Table 4-1). Oxytocin has no similar effect, even at high concentrations. AVP apparently is produced locally in both the adrenal cortex and the medulla together with its neurophysin, so that it acts as a paracrine factor for the stimulation of adrenal steroidogenesis. However, AVP is not present in the human fetal adrenal medulla, but appears to be present in the adult. After stimulation of steroidogenesis by AVP, steroid output decreases, and it appears that AVP desensitizes its receptor. There is evidence that AVP is synthesized in other organs also, such as the ovary, testis, uterus, thymus, and pancreas, where it probably also acts in a paracrine fashion. In addition to its effect in stimulating the release of Cortisol from the adrenal cortex, AVP has been reported to enhance the mitotic activity of

4. Posterior Pituitary Hormones

4. Posterior Pituitary Hormones


CO EPO pl<c

FIGURE 4-18 Cytoplasmic and nuclear signaling pathways of Vi vascular vasopressin receptors. Abbreviations: PLC, phospholipase C; PLD, phospholipase D; PLAz, phospholi-pase 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. Reproduced with permission from Thibonnier, M., Bayer, A.L., and Leng, Z. (1993). Regulatory Peptides 45, 79-84, 1993.


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