Vasopressin receptor distribution in the liver controls calcium wave propagation and bile flow

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...

Intercellular Ca2+Waves: Mechanisms and Function

“…Vasopressin is normally a strong trigger of bile secretion, but after 24 h of in vivo exposure to elevated vasopressin concentrations, a pulse of vasopressin triggered significantly less bile flow. This treatment removed the hepatocyte vasopressin receptor gradient in the perivenous area and impaired the ICWs, suggesting a link between the ICWs and bile flow (322). Adenoviral transfection of hepatocytes with the Ca 2ϩ -buffering protein parvalbumin reduced liver regeneration after partial hepatectomy and reduced norepinephrine-induced Ca 2ϩ oscillations, pointing to the importance of hepatocyte Ca 2ϩ signaling in liver regeneration (195).…”

Molecular Basis for Pacemaker Cells in Epithelia

“…Studies using isolated rat hepatocytes suggest that pacemaker cells synchronize Ca 2ϩ oscillations in pairs and triplets of cells, since oscillations are coordinated in such multiplets (46), and since one of the cells in a multiplet generally appears to set the rate of oscillations for its neighbors (45,47). Indirect evidence in both isolated hepatocytes (43,45) and the isolated perfused liver (11,14) suggests that this pacemaker activity may be driven by hormone receptor gradients. Here we examined this question directly in the liver-derived SkHep1 cell line.…”

“…Intercellular Ca 2ϩ signaling follows a complex pattern in the liver, much as it does in the heart. For example, vasopressin induces Ca 2ϩ waves that spread from pericentral to periportal hepatocytes, opposite to the direction of blood flow (7,9), and this may help direct canalicular motility and bile flow (11). Altered intercellular Ca 2ϩ signaling may contribute to the pathophysiology of certain disease states, since agents that block gap junction conductance also alter tissue function (12)(13)(14), and because certain cholestatic liver diseases are characterized by decreased expression of gap junctions and impaired transmission of intercellular Ca 2ϩ signals (15).…”

Desmopressin stimulates bile secretion in anesthetized rats

“…On the other hand ADH appears to stimulate bile flow during liver regeneration. It has been reported that V 1a vasopressin receptors gradient is correlated with choleretic effect of ADH (Serriere et al 2001). It has been documented that ADH after binding to V 1a vasopressin receptors activates enzyme phospholipase C, attached to the inside projection of the receptors.…”

“…Liver blood flow (Wang et al 1997), glycogenolysis and gluconeogenesis (Montero et al 2006) all are regulated by ADH. ADH in the perfused rat liver increases bile flow (Serriere et al 2001) and in the isolated rat hepatocyte couplets enhances bile secretory pressure and permeability of hepatocyte tight junctions (Nathanson et al 1992a;Schiff et al 1999). ADH decreases bile lipid secretion and canalicular secretion of taurocholate in cultured hepatocytes (Divald et al 1994;Schiff et al 1999).…”