No abstract

Arginine vasopressin elicits elaborate Ca 2+ signals in the liver (intercellular Ca 2+ waves), the functional implications of which are not understood. Waves propagate across hepatocyte plates following a lobular gradient in V1a vasopressin receptor density. Here, we report that changes in this receptor distribution control Ca 2+ wave propagation and bile flow. Although basal circulating vasopressin levels do not play a major role in the regulation of V1a receptor expression, increases in vasopressin concentration within physiological limits for 24 h can abolish the lobular gradient in V1a receptor, as assessed by spectrofluorimetry, videomicroscopy, binding studies, and RNase protection assays. In animals in which the V1a receptor gradient was abolished, intercellular Ca 2+ waves were impaired due to the equalization of Ca 2+ responses in the various zones of the lobule. In the isolated perfused liver, the early increase in vasopressininduced bile flow observed in control rats was much smaller if the V1a receptor density gradient was abolished. These findings suggest that V1a vasopressin receptor distribution controls intercellular Ca 2+ wave propagation and bile flow. The control of hormone receptor distribution in a tissue by an agonist may turn the signaling and function of this agonist on or off.Key words: intercellular signaling • cellular • heterogeneity • receptor • density • bile flow • vasopressin rginine vasopressin (AVP), in addition to having well-known antidiuretic effects, is involved in the regulation of many other functions, including liver processes such as ureogenesis, glycogenolysis, and neoglucogenesis (1-3). In the rat, the physiological impact of AVP stimulation in the liver is still a matter of debate, despite the fact that hepatocyte is one of the cell types richest in V1a AVP receptors (4). AVP, by activating the V1a receptor, induces increases in intracellular Ca 2+ concentration ([Ca 2+ ] i ), which may propagate among hepatocytes as intercellular waves, the complex mechanisms of which are beginning to be understood (5-7). In freshly isolated multicellular systems of hepatocytes and in the intact perfused liver, oriented Ca 2+ waves start in one cell and propagate towards the other cells on AVP stimulation (5,6,(8)(9)(10)(11)(12). We have recently suggested that this propagation follows a A gradient in sensitivity to the agonist. Each hepatocyte has its own density of hormone receptors, which results in a slight shift in phase of agonist-induced [Ca 2+ ] i increases with respect to neighboring cells. Intercellular calcium waves thus appear to be receptor-oriented in hepatocytes, a configuration comparable with cell-cell triggering in cardiac pacemaker cells (6, 7). This heterogeneity of Ca 2+ mobilization in adjacent hepatocytes results from an in situ gradient in the number of hormone receptors across the liver cell plate, as has been shown for the V1a vasopressin receptor, the density of which declines from the perivenous (PV) zone to the periportal (PP) area (6,9,13). The functional...