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From vasopressin receptor to water channel: intracellular traffic, constraint and by-pass.

The antidiuretic hormone vasopressin (VP) is synthesised in the magnocellular neurone cell bodies located in the hypothalamic supraoptic and paraventricular nuclei, and released into the general circulation from the nerve terminals in the posterior lobe of the pituitary gland (the neurohypophysis). Physiological control of the synthesis and release of VP is related mainly to changes in plasma osmolarity which are detected by specialised osmoreceptors in regions of the anterior hypothalamus which lie outside the blood–brain barrier e.g. in the subfornical organ and the organum vasculosa laminae terminalis (e.g. Thrasher et al. 1982, Yang et al. 1994). Although the precise pathways connecting osmoreceptor activation to VP release remain to be determined, nitric oxide is one molecule recently shown to be an inhibitory modulator of the hypothalamo–neurohypophysial system in response to osmotic stimuli (Ota et al. 1993, Yasin et al. 1993, Kadowaki et al. 1994, Wang & Morris 1996). In addition, an inhibitory pathway relates blood pressure to the release of VP, such that an increase either in arterial blood pressure detected by baroreceptors or in central venous pressure detected by cardiac volume receptors inhibits release of the hormone via a neuronal projection from the ventrolateral medulla (Head et al. 1987, McAllen & Blessing 1987). Other central projections are also involved in overall VP regulation. Although VP has physiological actions at multiple sites including the vasculature and the central nervous system, its principal physiological effect is the well-described increase in water reabsorption which takes place in the renal collecting ducts in the presence of an osmotic gradient resulting in an antidiuresis, hence its synonym antidiuretic hormone (ADH). Of the three principal receptors (V1a, V1b and V2) associated with the various effects of vasopressin, it is the V2 receptor which mediates the antidiuretic action in the collecting ducts. This receptor is located in the basolateral membranes of the vasopressin-sensitive principal cells of the inner (initial and terminal segments) and outer medullary collecting duct as well as the cortical arcades. The V2 receptor, cloned in the rat (Lolait et al. 1992) and in the human (Birnbaumer et al. 1992a), is a member of a family of proteins having seven intramembranous segments and three extracellular and four intracellular domains. The receptor is linked to adenylyl cyclase (AC) enzymes via heterotrimeric G proteins in the membrane; thus, AC is activated as a consequence of VP binding to its V2 receptor resulting in the formation of the second messenger cyclic AMP. Subsequent phosphorylation of protein kinase A is associated with the final step of water reabsorption. Cyclic AMP is rapidly degraded to 5*-AMP by intracellular phosphodiesterase enzymes. While various intermediate stages in the signalling pathway remain unclear, an important final step has recently been elucidated: the insertion of water channels into the apical (or luminal) membrane of the target cell, mediating rapid cross-membrane water transport. There is a family of water channels called aquaporins (AQP) which have been identified in plants and animals. Five of these membrane integral proteins are distributed in mammalian tissues ranging from erythrocytes to the lens of the eye where they mediate water transport (see Nielsen & Agre 1995, Knepper 1997), but only one (AQP2) is vasopressinsensitive. This recently cloned molecule (Fushimi et al. 1993) is located in the apical membranes of collecting duct cells, and within the cytoplasm, where they appear to be stored in vesicles called aggraphores (Harris et al. 1991, Nielsen et al. 1993). In the presence of VP there is an immediate increase in the presence of AQP2 in the apical membranes and an increased movement of aggraphores towards these membranes, followed by a longer-term increase in AQP2 production within the cells, as determined by immunofluorescence (Marples et al. 1995a). There is evidence that microtubules might be implicated in VP-stimulated water transport (Phillips & Taylor 1989), perhaps associated with the movement of aggraphores to the apical membrane. Furthermore, VP depolymerises the actin cytoskeleton of the apical membrane of rat inner medullary collecting duct cells, suggesting the possibility that the actin network might be associated with the fusion of aggraphores with the apical membrane (Simon et al. 361