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Highlights from the Literature

Edited by Christopher D. Verrico

Nominated by Michael Caplan
Yale University School of Medicine
michael.caplan{at}yale.edu

Question: What exo-endocytotic event is responsible for the retrieval of the vesicular membrane added to the plasma membrane following vesicle fusion?

Background: Neurotransmitters are released en masse via pores that form when the vesicular membrane fuses with the plasma membrane. There are two main theories on what occurs during the next phase, called exo-endocytosis, in which the vesicular membrane added to the plasma membrane is removed. The endocytotic cycle or compensatory endocytosis theory of vesicle recycling postulates that after neurotransmitter release the vesicular membrane collapses into and coalesces with the plasma membrane. A nascent clathrin-coated vesicle is then endocytotically formed. The reversible fusion or "kiss-and-run" theory postulates that the vesicle fuses briefly with the plasma membrane, allowing discharge of vesicle content before quickly resealing and recycling. Even though the kinetics of vesicle recycling differs between compensatory endocytosis (tens of seconds) and reversible fusion (milliseconds), they are thought to coexist and both be necessary for synaptic transmission.

Observations: Using electrophysiological capacitance measurements, Yamashita et al. determined that a rapid change in capacitance that is similar in magnitude and kinetics to kiss-and-run exo-endocytosis and has been suggested previously to correspond to it is unrelated to transmitter release in this experimental paradigm. A slower capacitance change (10–25 s) was measured and determined to be dependent on GTPase activity. Dynamin-1, which catalyzes the scission of clathrin-coated vesicles, was revealed as the GTPase necessary for synaptic transmission and vesicle recycling.

Significance: Yamashita et al. provide us with some insight into the molecular elements involved in exo-endocytosis by demonstrating that compensatory endocytosis is dynamin-1 dependent. They also found two distinct capacitance events: a fast type thought to represent reversible fusion and a slow type, compensatory endocytosis, that was release related and could occur independently of the former. Together, these results suggest that the primary process by which a neuron retrieves the vesicular membrane added to the plasma membrane following vesicle fusion is through compensatory endocytosis.

Nominated by Michael Caplan
Yale University School of Medicine
michael.caplan{at}yale.edu

Question: What is the genotype of transmembrane calcium channels in T cells?

Background: T cells, lymphocytes derived from the thymus, facilitate cell-mediated immunity and antibody production. Following antigen-induced activation of the T-cell, Ca²⁺ is released from intracellular stores, which in turn activates the Ca²⁺ release-activated Ca²⁺ (CRAC) channels in the plasma membrane. The ensuing influx of Ca²⁺ leads to activation of calcineurin (a phosphatase) and the dephosphorylation and translocation of the nuclear factor of activated T cells (NFAT), a transcription factor important for T cell development and function. The molecular identity of CRAC channels in T cells is unknown. In neurons, voltage-gated Ca²⁺ channels (Ca_v) are the primary route of Ca²⁺ influx and are essential for calcineurin activation and NFAT function; therefore, they could be important in lymphocytes. The Ca_v is a heteromultimer composed of ₁, ₂-, , and ß subunits. The major functional subunit ₁ is involved in pore-forming processes that are regulated via direct interactions with ß subunits.

Observations: T cells from wild-type mice were found to express three Ca_v1 family members: Ca_v1.1, Ca_v1.2, and Ca_v1.4. ß₄ and ₁ expression were confirmed and increased after T cell stimulation in wild-type T cells. It was further determined that the intrinsic responsiveness of these Ca_v1 channels to voltage was maintained, and upon depolarization there was a concomitant increase in channel opening. The lethargic mouse has a mutation in the ß₄ subunit with a resultant loss of the ₁ binding site and a significant inhibition of ß₄ expression. Analysis of mutant mouse T cells revealed significantly lower levels of ß₄ and Ca_v1.1 subunit expression. Functionally, mutant mouse T cells had an impaired Ca²⁺ response, which was also evident from the inhibition of transcription factor translocation and cytokine production.

Significance: Strong evidence is provided demonstrating an intimate relationship between T cell functions and the ß₄ subunit of Ca_v channels. Thus the initial intracellular influx of Ca²⁺ following T cell activation may be mediated by Ca_v channels comprised of ß₄ subunits. Given these results and the role of T cells in the recognition/rejection of foreign tissues and other pathological conditions, new therapeutic strategies could conceivably be developed that specifically target T cells based on the genotype of their channels.

Nominated by Baruch Kanner
Hebrew University Hadassah Medical School
kannerb{at}cc.huji.ac.il

Question: What can we learn about the active transport cycle of the sarco(endo)-plasmic reticulum Ca²⁺-ATPase (SERCA) from its crystal structure with a phosphate analog bound?

Background: SERCA catalyzes the ATP-dependent reuptake of cytosolic Ca²⁺ into the sarcoplasmic reticulum (SR) following muscle contraction. This active transport cycle is achieved by formation of the following states: 1) transition from E1 to a state with two Ca²⁺ ions bound on the cytoplasmic side of the SR membrane (E1•2Ca²⁺); 2) a phosphorylated state of E1•2Ca²⁺ necessary for ion transfer (E1•ATPE1P•ADPE1P), (3) transition to the E2P ground state, causing release of Ca²⁺ into the SR lumen and the uptake of protons; 4) formation of the E2 state when the cycle is completed by dephosphorylation of E2P (E2PE2•P_iE2); and 5) return to the E1 state following conversion from E2. Crystal structures of the E1•2Ca²⁺ state, the unbound Ca²⁺ state with the inhibitor thapsigargin [E2(TG)], and the intermediate state with Mg²⁺, Ca²⁺, and a non-hydrolyzable ATP analog bound (E1• AMPPCP) have been elucidated.

Observations: Here the crystal structure of the SERCA is described at 2.3-Å resolution in the absence of Ca²⁺ but with a bound phosphate analog (E2•MgF₄^2–). This likely depicts the structure at the E2 state after hydrolysis but before release of the phosphate (E2•Pi). Using this structure and the previously determined structures of the SERCA, the opening and closing of the luminal gate and the relationship with the phosphorylation site is described in terms of rearrangements of the 3 cytoplasmic domains and 6 out of 10 transmembrane helices.

Significance: Toyoshima and colleagues have provided yet another significant contribution to enhance our understanding of the SERCA catalytic cycle. The E2•MgF₄^2– form is hypothesized to reveal the luminal gating mechanism, and phosphate release is postulated to be the trigger inducing luminal gate closure.

Note that shortly after publication, Olesen et al. (Science 306: 2251–2255, 2004) published the structure of E2•AlF₄^–, which is similar to the one described here. According to Olesen and colleagues, the luminal gate in E2•AlF₄^– is closed, and consequently they propose a divergent theory of the active transport cycle. This study is also highlighted in this month’s issue of Physiology.

Nominated by Baruch Kanner
Hebrew University Hadassah Medical School
kannerb{at}cc.huji.ac.il

Question: Can a transitional state of sarco(endo)plasmic reticulum Ca²⁺-ATPase (SERCA) hydrolysis elucidate its luminal gating mechanism?

Background: SERCA catalyzes ATP-dependent transport of Ca²⁺ away from the cytosol, into the sarcoplasmic reticulum (SR) lumen to keep cytosolic Ca ²⁺ concentration low, allowing Ca²⁺ to serve as a signal. SERCA also pumps H⁺ as a countercation from the lumen and into the cytoplasm. SERCA is comprised of 10 transmembrane segments (M1– M10), which contain the two Ca²⁺ binding sites, and three cytoplasmic domains: actuator (transduction), nucleotide-binding, and phosphorylation domains. The functional cycle of the ATPase is described above (Toyoshima et al. Nature 432: 361–368, 2004). In this study, Olesen et al. describe the structural and functional changes that take place when a state analogous to E1P is converted to one reflecting the E2P:H₂O transitional state.

Observations: Similar to Toyoshima et al., Olesen et al. describe a crystal structure of the SERCA pump with a bound phosphate analog in the absence of Ca²⁺. Whereas Toyoshima et al. used a MgF₄^2– analog mimicking the product complex of hydrolysis, Olesen et al. describe the structure of the AlF₄^–-bound complex, which mimics the transition state of hydrolysis. Olesen et al. found that hydrolysis is based on an associative reaction mechanism similar to that of phosphoryl transfer from ATP. They also found that the E2•AlF₄^– form represents a closed, counterion-bound state. This is further backed up by biochemical data. Using this and previously identified structures, they pointed to the binding sites for the countertransported protons as the buried Asp and Glu residues that are also involved in Ca²⁺ binding in E1 states. They propose a model of the opening and closing of the luminal gate coupled to the conversion, in a preceding step, of the E2P ground state to the E2-P transition state.

Significance: Olesen et al describe a coupling mechanism between hydrolysis and countercation occlusion as inferred from an analysis of the E2•AlF₄^– state. As such, there are substantial discrepancies in the proposed synopses of SERCA ion pumping from the Toyoshima and Olesen consortiums. Foremost among these is the relationship between the closing of the luminal gate and dephosphorylation of the E2P state. Olesen suggests that the luminal gate is closed upon phosphoenzyme hydrolysis, whereas Toyoshima contends that release of the inorganic phosphate leaving group closes the luminal gate. We await further crystal structures, in particular that of E2•BeF₃^–, to resolve this matter.

Nominated by Jose Lopez-Barneo
Hospital Universitario Virgen del Rocio
jose.l.barneo.sspa{at}juntadeandalucia.es

Question: Why do in vitro and in vivo data differentially implicate iron regulatory protein (IRP) 1 or 2 as the primary factor in iron homeostasis?

Background: Iron homeostasis is regulated by iron-induced alterations in proteins involved in iron metabolism and cellular iron displacement. For example, in the absence of cellular iron the RNA motifs called iron responsive elements (IREs) bind IRP1 and IRP2, which modulates proteins such as ferritin (an iron storage protein) and the transferrin receptor (TfR; part of the intracellular transport mechanism of iron). In iron-replete cells, IRP2 is degraded but the bifunctional IRP1 interconverts citrate and isocitrate (an aconitase); its role as an aconitase is poorly understood. Empirical evidence from various cell lines implicates IRP1 as the major player in iron homeostasis. However, IRP1–/– mice display normal iron metabolism in most tissues, whereas IRP2–/– mice have increased ferritin expression and decreased TfR expression in multiple tissues due to reduced IRP binding to IREs. Some insight into this paradox is provided by Meyron-Holtz et al.

Observations: Macrophages cultured from IRP2–/– mice were unable to regulate iron (i.e., bind IREs) under physiological oxygen concentrations (3–6% O₂). Under atmospheric O₂ levels (21%), IRP1 compensated for the IRP2 deficiency, fully regulating ferritin and TfR expression. Conversely, ferritin and TfR regulation in IRP1–/– macrophages was normal at 3% O₂, suggesting that IRP2 was the main source of IRE binding under basal conditions. In contrast to data collected from macrophages, data collected from lymphocytes revealed that both IRP2 and IRP1 have significant functions in basal iron metabolism.

Significance: The conflicting data from cell lines and in vivo models appears to be a consequence of the experimental O₂ conditions. IRP1 senses iron only at high O₂ concentrations, leaving IRP2 as the major regulator of iron metabolism at basal physiological O₂ concentrations in most cells. The authors postulate that IRP1 may be a contributing factor in the pathology of some diseases such as Parkinson disease, which is associated with increased iron content and decreased ferritin. The pathological release of reactive O₂ species is hypothesized to convert IRP1 from its aconitase form to its IRE-binding form, inducing iron toxicity.

Nominated by Eve Marder
Editor, Journal of Neurophysiology
Brandeis University
marder{at}brandeis.edu

Question: Do 7- to 12-Hz oscillations in the gustatory cortex (GC) reflect disengagement from a task or anticipation of it?

Background: Oscillatory cortical activity recorded from rat primary somatosensory cortex reveals 7- to 12-Hz oscillations. These oscillations are similar to a form of generalized seizures known as "absence seizures" and are thus thought by some to represent a pathological state that impairs consciousness. Others theorize that these oscillations are benign physiological discharges that are analogous to the human somatosensory µ rhythm, which is characterized by an "idling" rhythm of motor cortex. Both of these theories support the disengagement hypothesis, which postulates that after a period of inactivity, movement triggers the animal out of the oscillatory state. However, there is an anticipation/processing hypothesis that proposes that these oscillations are associated with task orientation, i.e., that they specifically predict movement.

Observations: Animals with microelectrodes implanted bilaterally into their GC were trained in a task that was astutely designed to distinguish between two phases characterized by either task-oriented anticipation of stimuli or disengaged behavior. The task-oriented phase consisted of a waiting period followed by a period of anticipation and intense lever-pressing (collectively a 30-s period termed the foreperiod) that was rewarded with water after the 30 s had elapsed. The second disengaged phase was distinguished by a period of unorganized, almost random lever pressing during and after the foreperiod, which suggested that the animals were no longer seeking reward. After establishing that the GC expresses a 7- to 12-Hz rhythm, Fontanini and Katz demonstrated that these oscillations occurred exclusively during the disengaged phase and did not appear to be associated with physical or gustatory processes.

Significance: This work supports the idling disengagement hypothesis because the GC oscillations observed appear to be representative of a cortical state related to disengagement from task orientation. Conversely, these data do not support the disengagement theory that suggests the GC oscillations are epileptic in nature because animals were able to lever press and perform gustatory processes even after trials with rhythmic activity in the disengaged phase. Collectively, these studies strongly suggest that GC rhythms are not indicative of anticipation but are rather due to a nonpathological loss of attention.

Nominated by Angus Nairn
Associate Editor, Journal of General Physiology
Yale University School of Medicine
angus.nairn{at}yale.edu

Question: Do interacting proteins regulate the activity of ClC Cl^– channels?

Background: Found in organisms from bacteria to mammals, ClC voltage-gated Cl^– channels support diverse and fundamental physiological processes. Knockout studies in mice have helped elucidate the physiological roles of ClCs, and the association of ClC gene mutations with several human diseases underscores their functional importance. Recently, the nematode Caenorhabditis elegans was found to express a hyperpolarization-activated ClC channel encoded by the clh-3 gene. A channel splice variant, CLH-3b, is expressed in the worm oocyte and is activated during oocyte meiotic cell cycle progression and in response to cell swelling. Cell cycle- and swelling-induced channel activation occurs by type 1 protein phosphatase-mediated serine/threonine dephosphorylation. Other proteins that regulate CLH-3b and that comprise physiologically relevant regulatory signaling pathways were sought.

Observations: Denton and coworkers performed yeast two-hybrid analysis and revealed that germinal center kinase-3 (GCK-3), a new member of the sterile 20 (Ste20) serine/threonine kinase superfamily, interacts with the channel’s COOH terminus. CLH-3b expressed in human embryonic kidney 293 cells alone was constitutively active, whereas coexpression with GCK-3 caused phosphorylation-dependent inhibition of channel activity. A physical interaction between GCK-3 and CLH-3b via a four-amino-acid binding motif was required for channel regulation. Both fast and slow kinetic processes described hyperpolarization-induced gating of constitutively active CLH-3b, whereas gating in kinase-inhibited channels was dominated by a single slow kinetic mechanism. Single oocyte RT-PCR and green fluorescent protein transcriptional reporters demonstrated that GCK-3 and CLH-3b were coexpressed in the worm oocyte and excretory cell, which functions in fluid secretion. Knockdown of GCK-3 expression by RNA interference demonstrated that the kinase functions to inhibit CLH-3b activity in nonmaturing worm oocytes.

Significance: These findings implicate Ste20 kinases in the regulation of ClC channel activity and associated physiological processes. Convincing evidence is presented demonstrating that GCK-3 is an interacting partner of CLH-3b and that it mediates cell cycle- and volume-dependent channel inhibition by phosphorylating serine/threonine residues on the channel itself and/or associated regulatory proteins. The findings of Denton et al. suggest novel mechanisms for coupling cell volume changes to cell cycle events and for coordinately regulating the activity of ion channels and transporters that control cellular Cl^– content, cell volume, and epithelial fluid secretion.

Nominated by Pontus Person
Editor, American Journal of Physiology-Regulatory,
Integrative, and Comparative Physiology
Humboldt University
pontus.person{at}charite.de

Question: Can leptin perfused into the upper gastrointestinal tract reduce food intake?

Background: The protein product of the obese (Ob) gene, leptin (from Greek leptos, meaning "thin") is the major player in the regulation of adipose tissue, acting as a negative feedback signal to reduce food intake and increase energy expenditure. Leptin is synthesized by white adipose cells and cells in the gastric mucosa, but unlike adipose-derived leptin, gastric leptin is stored and rapidly secreted in response to food intake and cholecystokinin (CCK), a gut peptide secreted in response to dietary nutrients that reduces food intake via actions on abdominal vagal afferent neurons. In addition, although leptin receptors (Ob-R) in the central nervous system have traditionally been associated with leptin’s effects, Ob-R mRNA expression has recently been detected in afferent neurons of the vagus nerve. Together, these data suggest that leptin may act in a paracrine fashion directly on vagal afferent neurons to signal satiety.

Observations: Leptin was infused into the celiac artery, which perfuses the stomach and other abdominal organs, or into a jugular vein to determine whether gastric leptin could reduce food consumption. Although plasma levels were similar, leptin rapidly and selectively inhibited short-term (30-min) food intake after intraceliac infusion but not intrajugular infusion, which suggests an effect independent from leptin’s actions in the brain. To further support this argument, Peters et al. determined that this leptin-induced effect was precluded by removing gastric vagal innervation or systemic capsaicin administration (capsaicin destroys unmyelinated afferent neurons in the vagus and spinal nerves). Notably, when leptin was co-infused with CCK, there was a rapid and synergistic reduction in food intake.

Significance: Although the exact site of action for gastric leptin is still unknown, these data provide strong evidence that exogenously administered leptin can act peripherally on capsaicin-sensitive vagal afferents that innervate structures below the diaphragm to reduce short-term food intake; however, this has not been tested directly. Thus, in addition to the well-documented long-lasting (24-h) central effects of adipose-derived leptin on satiety, gastric-derived leptin may represent a novel, acute, and rapid mechanism to modulate food intake via interactions with vagal afferents. Identifying the site(s) of gastric leptin’s action may provide novel targets for the treatment of obesity.

Nominated by Stewart Sage
Chair, Editorial Board, Journal of Physiology
University of Cambridge
SOS.10{at}cam.ac.uk
Communicated by Stefano Vicini
Georgetown University
svicin01{at}georgetown.edu

Question: Does subunit genotype underlie the divergent properties of N-methyl-D-aspartate (NMDA) receptors?

Background: NMDA glutamate receptors are ligand-gated ion channels composed of NR1 and NR2 subunit assemblies that undergo multiple conformational changes upon agonist binding. NR2 subunits are one of four separate gene products (NR2A–D) whose expression is regulated spatially, temporally, and by activity. Recently, the NR2A subunit has been associated with long-term potentiation and the NR2B subunit has been associated with long-term depression. Besides this distinction, there are several functional differences between NR2A and NR2B subunits, such as the time course of agonist-induced activation/deactivation and excitatory postsynaptic currernt decay; both are slower in NR2B subunit-containing receptors. Moreover, peak open probability is higher for NR2A subunit receptors. These differences are exemplified in the developmental shift from NR2B expression in adolescents to mixed NR2A and NR2B expression in adults, which is correlated with kinetic speeding of NMDA receptor-mediated synaptic currents.

Observations: In the paper by Erreger et al., the authors investigated molecular mechanisms of differential NMDA receptor-mediated synaptic currents using a powerful approach that allowed the parameters of a kinetic mechanism describing receptor behavior to be estimated. Recordings suggested that NR1-NR2A and NR1-NR2B underwent multiple conformational changes; the rate constant for at least one of these transitions was faster for NR1-NR2A. This influenced channel open probability, which was greater for NR1-NR2A. A model was developed that incorporated two pregating activation steps, which accounted for NR1-NR2A or NR1-NR2B currents and predicted peak open probability. A model also predicted that NR2B is more effective at raising intracellular calcium at low frequencies (induces long-term potentiation), whereas NR2A is more effective at mediating calcium signaling in response to high frequencies (induces long-term depression).

Significance: These data suggest that a NR2 subunit’s genotype regulates at least one of the conformational changes NMDA receptors undergo before channel gating. Additionally, the differences in the time course for calcium entry derived from the model may explain the subunits’ distinct roles in synaptic plasticity. These results make a major contribution to understanding differences in signaling mechanisms underlying synaptic plasticity.

Nominated by Stewart Sage
Chair, Editorial Board, Journal of Physiology
University of Cambridge
SOS.10{at}cam.ac.uk
Communicated by William Large and Anthony Albert
largew{at}sghms.ac.uk

Question: How does Ca²⁺ modulate canonical transient receptor potential channel (TRPC) activity?

Background: Receptor-operated Ca²⁺-permeable (ROC) channels have properties similar to the TRPC family of cation channels. In fact, TRPC6 has recently been theorized to function as a ROC channel subunit. TRPCs are differentially regulated by protein kinase C (PKC), inositol 1,4,5-triphosphate (IP₃), diacylglycerol, external Ca²⁺ ([Ca²⁺]_o), and internal Ca²⁺ ([Ca²⁺]_i). Recent reports have suggested that a Ca²⁺-calmodulin (CaM)-mediated mechanism is also involved in TRPC modulation. So, although available data suggest that there is a complex regulatory system for TRPCs, little is known regarding how Ca²⁺ and other factors modulate a specific TRPC’s activity.

Observations: Human embryonic kidney 293 cells were transfected with murine TRPC6 or TRPC7 (a TRPC6 homolog), and their currents were monitored by whole-cell and single-channel patch-clamp recordings. TRPC7 and TRPC6 were differentially affected by Ca²⁺. TRPC6 were biphasically affected by [Ca²⁺]_o, being potentiated by low [Ca²⁺]_o and inhibited at high [Ca²⁺]_o, whereas TRPC7 density currents were simply inhibited by [Ca²⁺]_o. Low [Ca²⁺]_i enhanced TRPC6 and 7 activities, but as [Ca²⁺]_i increased, activity was attenuated. CaM-dependent phosphorylation of TRPC6, possibly via CaM kinase II, was essential for TRPC6 activity, whereas inhibition of CaM enhanced TRPC7 activity. Modulation of PKC activity revealed its involvement in the inactivation of TRPC6 and 7 by high [Ca²⁺]_i. Finally, IP₃ enhanced TRPC7 activity but was without effect on TRPC6.

Significance: This study describes the regulation of TRPC6 and 7 channels by Ca²⁺ and Ca²⁺-dependent mechanisms, which are also important for receptor-operated Ca²⁺ influx in vascular smooth muscle. The authors provide compelling evidence that a priming phosphorylation process involving CaM kinase II, probably at the TRPC6 channel protein, is essential for activation of TRPC6. This exciting discovery may indicate that CaM kinase II or other kinases may be involved in phosphorylation priming events that are necessary for activation of other TRP or ROC channel proteins.

Nominated by Jeff Sands
Editor, American Journal of Physiology-Renal
Physiology
Emory University School of Medicine
jsands{at}emory.edu

Question: Does collecting duct (CD)-derived endothelin-1 (ET-1) affect renal water excretion?

Background: ET-1 belongs to a group of peptide hormones that are released by endothelial cells and are the most potent vasoconstrictors known. ET-1 synthesis in the kidneys takes place in the CD, where in vitro data implicate it as an autocrine inhibitor of vasopressin (AVP)-stimulated water reabsorption. However, direct in vivo evidence supporting an autocrine role of ET-1 in the regulation of CD water transport has proven difficult to obtain.

Observations: Ge et al. sagaciously used Cre-lox methodology to develop a CD-specific knockout of ET-1 to circumvent the lethality of traditional gene knockouts of the ET system. Through the use of careful physiological studies, they were able to tease out a subtle phenotype in a knockout mouse. They found that under basal conditions plasma AVP levels were significantly lower in the ET-1 knockout mice, whereas urine volume and osmolality were unaffected, even in response to a chronic water load. The implied increased responsiveness to AVP in the knockout mice was confirmed by demonstrating an enhanced antidiuretic response to AVP. The physiological relevance of the enhanced AVP responsiveness was demonstrated in knockout mice, which exhibited impaired responses to acute water loading (i.e., reduced water excretion) and an attenuated increase in CD ET-1 production during this acute phase. Finally, evidence was provided to support the contention that the augmented AVP response was due, at least in part, to postreceptor mechanisms.

Significance: These results illustrate the interplay of multiple factors in regulating water excretion and demonstrate how careful physiological studies using the right model can advance our understanding of complex regulatory pathways. They provide the first direct indication of a physiological role of a peptide not directly involved in water transport in the regulation of renal water excretion in vivo. The current in vivo data and previous in vitro data implicate ET-1 as an autocrine regulator of AVP action in the CD. Therefore, future efforts will undoubtedly be aimed at elucidating the postreceptor mechanisms involved in ET-1 modulation of AVP responsiveness and/or if ET-1 acts in a paracrine manner to regulate renal water excretion.

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