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Symposium Reports |
1 Department of Psychology, State University of New York at Buffalo, Buffalo, NY 14260, USA 2 Department of Animal Biology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104, USA
Abstract
Angiotensin II plays a key role in the regulation of body fluid homeostasis. To correct body fluid deficits that occur during hypovolaemia, an animal needs to ingest both water and electrolytes. Thus, it is not surprising that angiotensin II, which is synthesized in response to hypovolaemia, acts centrally to increase both water and NaCl intake. Here, we review findings relating to the properties of angiotensin II receptors that give rise to changes in behaviour. Data are described to suggest that divergent signal transduction pathways are responsible for separable behavioural responses to angiotensin II, and a hypothesis is proposed to explain how this divergence may map onto neural circuits in the brain.
(Received 22 December 2006;
accepted after revision 14 February 2007; first published online 28 February 2007)
Corresponding author D. Daniels: B74 Park Hall/Psychology, University at Buffalo, Buffalo, NY 14260, USA. Email: danielsd{at}buffalo.edu
Regulation of body fluid homeostasis is critical for survival. Imbalance in body fluid occurs when the extracellular electrolyte concentration increases, drawing water from the cell, or when the volume of the extracellular fluid decreases. Owing to the water compartment affected, these situations have been described as intracellular and extracellular dehydration, respectively. Although both types of dehydration are characterized by decreased volume, the nature of the loss in each poses different challenges to the animal. In either circumstance, physiological responses act to slow or prevent further loss of fluid, but behavioural responses are required to restore homeostasis. Since the needs of the animal differ depending on the type of dehydration, the behavioural responses must, and do, take different forms. Consumption of water is needed in both cases, but restoration of extracellular dehydration must also include sodium chloride, lest the extracellular fluid become too dilute. As such, the different responses are commonly referred to as osmotic (intracellular) or hypovolaemic (extracellular) thirst. Unlike other presentations in this symposium, which focused mostly on responses to osmotic challenges (Bourque et al. 2007; Liedtke, 2007; Noda, 2007), the data described here are more relevant to the changes in behaviour induced by extracellular dehydration. Specifically, we will focus on the receptor mechanisms involved in the detection of peripheral renin–angiotensin system activity by the brain.
Renin–angiotensin system activity begins with the rate-limiting step of renin synthesis and release from the juxtaglomerular cells of the kidney (Catanzaro et al. 1983). The regulation of renin synthesis and release is governed by several stimuli, including hypovolaemia (Zehr et al. 1980). Once released, renin produces angiotensin I as a cleavage product of angiotensinogen, a large liver glycoprotein that is continuously released and readily available in the plasma. Angiotensin I is further processed by angiotensin converting enzyme (ACE) into the bioactive angiotensin II. Angiotensin II has many biological functions with diverse targets, including vascular smooth muscle, adrenal cortex, kidney and brain (e.g. Aquitlera & Marusic, 1971; Peach, 1977; Catt et al. 1987). Included in a list of central actions, angiotensin II stimulates water intake. The dipsogenic properties of angiotensin II were first demonstrated using intravenous or central injections of angiotensin II in rats (Epstein et al. 1969, 1970; Fitzsimons & Simons, 1969; Hsiao et al. 1977). These studies and many that followed clearly demonstrated that even in the hydrated rat, injections of angiotensin II lead to marked and rapid increases in water intake. In fact, the effect of angiotensin II on water intake is so reliable and robust that angiotensin II injections are used by many laboratories to verify cannula placement in the forebrain ventricles.
In addition to the increases in water, animals treated with angiotensin II also increase consumption of NaCl solutions (Buggy & Fisher, 1974; Avrith & Fitzsimons, 1980; Bryant et al. 1980). Angiotensin II-induced intake of NaCl generally occurs after a delay and is more likely to occur in mineralocorticoid-treated animals (Fluharty & Epstein, 1983). Nevertheless, relatively rapid increases in NaCl have been observed after angiotensin II treatment, especially when animals are presented with lower concentrations of NaCl (Buggy & Fisher, 1974) or when oxytocin receptor antagonists are also provided (Stricker & Verbalis, 1996). The subtle differences may reflect direct and indirect effects of angiotensin II that remain to be explored, but it is quite clear that angiotensin II has the ability to stimulate intake of NaCl directly.
The actions of angiotensin II occur through binding to cell surface receptors. Two main subtypes of angiotensin II receptors have been cloned, and are termed the type I (AT1) and type II (AT2) receptors (Murphy et al. 1991; Kambayashi et al. 1993). Both types of receptors have a seven transmembrane domain motif and both have been shown to couple to G proteins (de Gasparo et al. 2000). Although the two receptor subtypes bind angiotensin II with nearly identical affinity, homologous residues account for just over 30% (de Gasparo, 2002). Moreover, the functional roles of the receptors appear to be quite different, with the majority of evidence pointing to the AT1 receptor as key for the behavioural responses to angiotensin II. For example, angiotensin II-induced water intake was blocked by an AT1 receptor antagonist but persisted when animals were pretreated with an AT2 receptor antagonist (Weisinger et al. 1997). Furthermore, antisense oligonucleotides designed to block AT1 receptor expression attenuated angiotensin II-induced water intake in a dose-dependent manner (Sakai et al. 1994).
Expression of AT1 receptors has been demonstrated in a variety of tissues, including adrenal gland, brain, heart, kidney, prostate and vasculature (Allen et al. 1990; Song et al. 1992; Zhuo et al. 1992; Montiel et al. 1993; Saavedra et al. 1993). Expression within the brain has been detected in a number of regions but most notably in the forebrain circumventricular structures, organum vasculosum of the lamina terminalis (OVLT) and subfornical organ (SFO; Mendelsohn et al. 1984; Song et al. 1992; Giles et al. 1999). Expression of AT1 receptors in these structures is notable because it provides a parsimonious explanation of how the peripherally derived angiotensin II can act on the brain without evidence of transport across the blood–brain barrier. The presence of AT1 in the circumventricular organs has been demonstrated using numerous techniques. Examples include receptor autoradiography (Mendelsohn et al. 1984; Shelat et al. 1998) and angiotensin II-induced Fos expression (Rowland et al. 1996), as well as recent pilot studies that used reverse transcription polymerase chain reaction on microdissected SFO tissue (Daniels & Fluharty, 2004).
The behavioural relevance of angiotensin II acting at the SFO and the OVLT has been a subject of many studies. Mangiapane & Simpson (1980) demonstrated increased water intake after injection of small amounts of angiotensin II into the SFO, whereas similar doses produced less or no water intake when injected into the nearby ventral fornical commissure or into the third ventricle. Lesions placed in the SFO blocked angiotensin II-induced water intake (Simpson & Routtenberg, 1973), suggesting that the SFO is a critical structure for the dipsogenic actions of angiotensin II. In contrast, a variety of studies have demonstrated the requirement of the OVLT and the surrounding anteroventral region of the wall of the third ventricle. For example, experiments by Buggy, Johnson and Fisher (Buggy & Fisher, 1976; Buggy & Johnson, 1977) provided evidence that periventricular structures, probably including OVLT, are also important for angiotensin II-induced water intake.
A good deal is known about the responses to angiotensin II at the cellular level. As stated previously, the AT1 receptor is a prototypical G protein-coupled receptor with well-documented coupling to Gq (de Gasparo et al. 2000). Stimulation of this receptor leads to activation of phospholipase C and the subsequent formation of diacylglycerol (DAG) and inositol trisphosphate (IP3), which lead to increased protein kinase C (PKC) activity and an increase in levels of free intracellular calcium, respectively. In addition to this traditionally transcribed pathway, AT1 receptor activation has also been shown to activate mitogen-activated protein (MAP) kinase family members, specifically p42/44 MAP kinase, also known as ERK1/ERK2 (Sadoshima et al. 1995). Although Gq-mediated pathways have been connected to MAP kinase activation in several systems, including one study demonstrating the requirement for PKC (Chiu et al. 2003), a series of experiments using AT1 receptor point mutants suggested that the activation of MAP kinase and the formation of the second messengers IP3 and DAG can occur independently. Specifically, conversion of the aspartate at the 74th position in the second transmembrane domain to asparagine, or conversion of the tyrosine at the 292nd position in the seventh transmembrane domain to phenylalanine, created a receptor that failed to stimulate IP3 formation after angiotensin II exposure but continued to stimulate MAP kinase activation (Hines et al. 2003). Moreover, in vitro approaches have demonstrated that a double isoleucine-substituted form of angiotensin II (Sar1,Ile4,Ile8-angiotensin II; abbreviated as SII) failed to stimulate IP3 formation while increasing levels of activated MAP kinase (Holloway et al. 2002; Wei et al. 2003; Miura et al. 2004). More recently, we have used this compound in AT1 receptor-transfected COS-1 cells and confirmed that stimulation of MAP kinase occurred without IP3 formation. In addition, we extended these data to show, for the first time, that SII antagonized angiotensin II stimulation of IP3 formation (Daniels et al. 2005), leading to the description of this modified angiotensin II as a signalling-selective AT1 receptor agonist (Yee et al. 2006).
The presence of signalling-selective agonists is not unique to the AT1 receptor. In fact, a review of the literature by Kenakin (2003) reveals evidence for ligand-selective receptor conformations in many receptor types, including those for dopamine, substance P, opioids, cholecystokinin, serotonin and others. Like these receptor systems, and the system involving gonatrophin-releasing hormone (GnRH) receptors (Lu et al. 2005), modifications to the ligand can lead to the activation of one intracellular signalling pathway or another. It is likely that these different signalling responses are governed by ligand-selective stabilization of different active states of the receptor. In some cases, including GnRH, multiple forms of the ligand are found endogenously, producing remarkable diversity of function (Millar, 2005). Evidence for this diversity of signalling has not, as yet, been shown with endogenously expressed angiotensin II, but the development of modified forms of angiotensin II has at least provided the opportunity to investigate the role of AT1 receptor signalling molecules on the multiple behaviours stimulated by angiotensin II.
Taking advantage of the signalling-selective agonist for the AT1 receptor, we demonstrated that injections of SII failed to increase water intake but increased NaCl intake in male rats (Daniels et al. 2005). Examination of MAP kinase activation in the brains of rats treated with angiotensin II, SII or vehicle was consistent with the above-mentioned findings from in vitro experiments and showed that either angiotensin II or SII increased levels of activated MAP kinase. Measures of Fos immunoreactivity, however, were markedly different in brains from rats treated with angiotensin II or with SII. Specifically, angiotensin II stimulated Fos expression in several forebrain areas, including the OVLT, SFO and supraoptic nucleus, that were virtually devoid of Fos-immunoreactivity in animals treated with SII or vehicle. A previous finding (Clark et al. 1992; Huang et al. 1998) that angiotensin II-induced Fos expression required calcium may provide some insight into this result. Specifically, SII failed to stimulate IP3 formation in vitro, and IP3 formation leads to the increase in free intracellular calcium. Thus, it is likely that the lack of Fos expression in the animals treated with SII reflects the failed stimulation of the Gq–PLC–IP3 pathway by this ligand (Daniels et al. 2005).
Taken together, the in vivo experiments led to our working hypothesis that AT1 receptor-stimulated signalling molecules have separable behavioural impacts. Treatment with angiotensin II, through stimulation of both the Gq–PLC–IP3 and MAP kinase pathways, leads to increased intake of both water and NaCl solution. Treatment with SII, which stimulates only the MAP kinase pathway, failed to stimulate water intake but increased consumption of saline. Moreover, recent preliminary experiments have used pretreatment with PD98059, an inhibitor of MAP kinase activation, in conjunction with angiotensin II. These experiments suggest that blockade of the MAP kinase pathway, without affecting the IP3 pathway, permit the dipsogenic action of angiotensin II but prevent its natriorexigenic properties.
Together, these data provide interesting insight into the behavioural relevance of angiotensin II intracellular signalling cascades; however, a number of questions remain to be addressed. Perhaps most important, how is it that a single group of cells, all expressing the AT1 receptor and all responding in similar fashion to angiotensin II, give rise to different ingestive behaviours? Is the IP3 pathway relevant to one subset of cells, whereas the activation of MAP kinase is more relevant to another, although angiotensin II activates both pathways in all of the cells? Perhaps angiotensin II-responsive cells in the OVLT and/or SFO fall into two categories, those that generate a neural event gated by the PLC–IP3–PKC pathway and those that rely on the MAPK pathway to induce a neural event. This suggestion, illustrated in Fig. 1, would explain how the separate signal transduction pathways generate the separable behaviours. In contrast, it is possible that the Gq–PLC–IP3- and MAPK-mediated events occur in the same cell, but the behavioural data indicate that the consequences of the two pathways diverge at some point. Determining the nature of this divergence is an important problem that must be addressed if we are to understand how angiotensin receptor signalling leads to specific changes in ingestive behaviour.
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Acknowledgements
The experiments described here were conducted with support from the National Institutes of Heath awards DK064012 [GenBank] (D.D.), DK073800 [GenBank] (D.D.), HL058792 (D.K.Y.) and DK052018 [GenBank] (S.J.F.).
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