WNK signalling pathways in blood pressure regulation

Hypertension (high blood pressure) is a major public health problem affecting more than a billion people worldwide with complications, including stroke, heart failure and kidney failure. The regulation of blood pressure is multifactorial reflecting genetic susceptibility, in utero environment and external factors such as obesity and salt intake. In keeping with Arthur Guyton’s hypothesis, the kidney plays a key role in blood pressure control and data from clinical studies; physiology and genetics have shown that hypertension is driven a failure of the kidney to excrete excess salt at normal levels of blood pressure. There is a number of rare Mendelian blood pressure syndromes, which have shed light on the molecular mechanisms involved in dysregulated ion transport in the distal kidney. One in particular is Familial hyperkalemic hypertension (FHHt), an autosomal dominant monogenic form of hypertension characterised by high blood pressure, hyperkalemia, hyperchloremic metabolic acidosis, and hypercalciuria. The clinical signs of FHHt are treated by low doses of thiazide diuretic, and it mirrors Gitelman syndrome which features the inverse phenotype of hypotension, hypokalemic metabolic alkalosis, and hypocalciuria. Gitelman syndrome is caused by loss of function mutations in the thiazide-sensitive Na/Cl cotransporter (NCC); however, FHHt patients do not have mutations in the SCL12A3 locus encoding NCC. Instead, mutations have been identified in genes that have revealed a key signalling pathway that regulates NCC and several other key transporters and ion channels in the kidney that are critical for BP regulation. This is the WNK kinase signalling pathway that is the subject of this review.     

Neurotrophin signalling pathways regulating neuronal apoptosis

Recent evidence indicates that naturally occurring neuronal death in mammals is regulated by the interplay between receptor-mediated prosurvival and proapoptotic signals. The neurotrophins, a family of growth factors best known for their positive effects on neuronal biology, have now been shown to mediate both positive and negative survival signals, by signalling through the Trk and p75 neurotrophin receptors, respectively. The mechanisms whereby these two neurotrophin receptors interact to determine neuronal survival have been difficult to decipher, largely because both can signal independently or coincidentally, depending upon the cell or developmental context. Nonetheless, the past several years have seen significant advances in our understanding of this receptor signalling system. In this review, we focus on the proapoptotic actions of the p75 neurotrophin receptor (p75NTR), and on the interplay between Trk and p75NTR that determines neuronal survival.     

Electrophysiology of mammalian hypothalamic and interpeduncular neurons in vitro

Summary Electrical activities of the hypothalamic and interpeduncular neurons were studied in vitro in brain slices prepared from the guinea-pig brain stem. Neurons preserved resting membrane potentials comparable to those of neurons in vivo, responded to stimulation of the afferent fibres, and retained stable spontaneous firings for more than several hours.     

The hypothalamic somatostatinergic pathways mediate feeding behavior in the rat

The level of somatostatin in the hypothalamus was higher in satiated rats than in hungry rats. Elevating hypothalamic somatostatin levels by administering somatostatin into the hypothalamus produced a decrease in food intake, whereas lowering hypothalamic somatostatin levels by administering cysteamine into the peritoneal cavity produced an increase in food intake in rats.     

Electrophysiology of mammalian hypothalamic and interpeduncular neurons in vitro.

Electrical activities of the hypothalamic and interpeduncular neurons were studied in vitro in brain slices prepared from the guinea-pig brain stem. Neurons preserved resting membrane potentials comparable to those of neurons in vivo, responded to stimulation of the afferent fibres, and retained stable spontaneous firings for more than several hours.     

Fluorescence histochemical demonstration of the uptake of dopamine-derived dihydroisoquinoline in the hypothalamic neurons

Summary The uptake and the accumulation of dopamine-derived fluorescent dihydroisoquinoline were demonstrated with direct fluorescence histochemistry in the hypothalamic dopaminergic neurons, in the nerves of the neurointermediate lobe, and in some endocrine cells of the hypophysis of the rat.     

Insulin acts on the hypothalamic glucose-facilitated neurons to induce hyperglycemia and hyperinsulinemia in the rat

Microinjection of insulin (0.04-0.12 IU/microliter) into the anterior hypothalamus or the lateral hypothalamus, but not the ventromedial hypothalamus of the rat brain, caused a dose-dependent rise in blood glucose and in serum insulin. The majority (71.5%) of the glucose-facilitated neurons recorded in the lateral hypothalamic area were excited by intracerebral injection of insulin. The data indicate that insulin acts on the hypothalamic glucose-facilitated neurons to induce hyperglycemia and hyperinsulinemia. It is unknown whether insulin normally reaches the hypothalamic area, or how it might do so.     

Insulin acts on the hypothalamic glucose-facilitated neurons to induce hyperglycemia and hyperinsulinemia in the rat

Microinjection of insulin (0.04–0.12 IU/l) into the anterior hypothalamus or the lateral hypothalamus, but not the vertromedial hypothalamus of the rat brain, caused a dose-dependent rise in blood glucose and in serum insulin. The majority (71.5%) of the glucose-facilitated neurons recorded in the lateral hypothalamic area were excited by intracerebral injection of insulin. The data indicate that insulni acts on the hypothalamic glucose-facilitated neurons to induce hyperglycemia and hyperinsulinemia. It is unknown whether insulin normally reaches the hypothalamic area, or how it might do so.This work was supported by grants from the National Science Council (Taipei, Taiwan, Republic of China).     

Activation of stress signalling pathways enhances tolerance of fungi to chemical fungicides and antifungal proteins

Fungal disease is an increasing problem in both agriculture and human health. Treatment of human fungal disease involves the use of chemical fungicides, which generally target the integrity of the fungal plasma membrane or cell wall. Chemical fungicides used for the treatment of plant disease, have more diverse mechanisms of action including inhibition of sterol biosynthesis, microtubule assembly and the mitochondrial respiratory chain. However, these treatments have limitations, including toxicity and the emergence of resistance. This has led to increased interest in the use of antimicrobial peptides for the treatment of fungal disease in both plants and humans. Antimicrobial peptides are a diverse group of molecules with differing mechanisms of action, many of which remain poorly understood. Furthermore, it is becoming increasingly apparent that stress response pathways are involved in the tolerance of fungi to both chemical fungicides and antimicrobial peptides. These signalling pathways such as the cell wall integrity and high-osmolarity glycerol pathway are triggered by stimuli, such as cell wall instability, changes in osmolarity and production of reactive oxygen species. Here we review stress signalling induced by treatment of fungi with chemical fungicides and antifungal peptides. Study of these pathways gives insight into how these molecules exert their antifungal effect and also into the mechanisms used by fungi to tolerate sub-lethal treatment by these molecules. Inactivation of stress response pathways represents a potential method of increasing the efficacy of antifungal molecules.     

Increase in the hypothalamic tyrosine hydroxylase activity after lesion of the catecholaminergic neurons of the rat pontine tegmentum]

Hypothalamic tyrosine hydroxylase activity is increased 6 and 18 h after bilateral lesioning of the Locus Coerulues, in the Rat. An adrenocortical hypertrophy was observed previously, under the same experimental conditions. The neurochemical and neuroendocrinological implications of theses results are discussed.     

Interaction between the effects of centrally administered arecoline and leucocyte pyrogen on the activity of posterior hypothalamic neurons in the rabbit

Summary In experiments with urethane-anesthetized rabbits, the alteration in the activity of posterior hypothalamic neurons resulting from intracerebroventricular injection of leucocyte pyrogen was attentuated by subsequent administration of arecoline. Atropine failed to alter the neuronal response to leucocyte pyrogen but abolished the effect of arecoline. The neuronal response to arecoline was reversed in the absence of leucocyte pyrogen.     

Interaction between the effects of centrally administered arecoline and leucocyte pyrogen on the activity of posterior hypothalamic neurons in the rabbit

In experiments with urethane-anesthetized rabbits, the alteration in the activity of posterior hypothalamic neurons resulting from intracerebroventricular injection of leucocyte pyrogen was attenuated by subsequent administration of arecoline. Atropine failed to alter the neuronal response to leucocyte pyrogen but abolished the effect of arecoline. The neuronal response to arecoline was reversed in the absence of leucocyte pyrogen.     

Gonadotrophic activity in hypothalamic extracts

Résumé Si l'on administre à des rats stériles par testostérone des extraits hypothalamiques de mouton préparés suivant la technique deGuillemin, on déclenche l'apparition des corps jaunes aussi bien chez les rats entiers que chez les animaux privés d'hypophyse. Ces extraits ont une activité gonadotrophique intrinsèque.     

Sphingolipids in mammalian cell signalling

Sphingolipids and their metabolites, ceramide, sphingosine and sphingosine-1-phosphate, are involved in a variety of cellular processes including differentiation, cellular senescence, apoptosis and proliferation. Ceramide is the main second messenger, and is produced by sphingomyelinase-induced hydrolysis of sphingomyelin and by de novo synthesis. Many stimuli, e.g. growth factors, cytokines, G protein-coupled receptor agonists and stress (UV irradiation) increase cellular ceramide levels. Sphingomyelin in the plasma membrane is located primarily in the outer (extracellular) leaflet of the bilayer, whilst sphingomyelinases are found at the inner (cytosolic) face and within lysosomes/endosomes. Such cellular compartmentalisation restricts the site of ceramide production and subsequent interaction with target proteins. Glycosphingolipids and sphingomyelin together with cholesterol are major components of specialised membrane microdomains known as lipid rafts, which are involved in receptor aggregation and immune responses. Many signalling molecules, for example Src family tyrosine kinases and glycosylinositolphosphate-anchored proteins, are associated with rafts, and disruption of these domains affects cellular responses such as apoptosis. Sphingosine and sphingosine-1-phosphate derived from ceramide are also signalling molecules. In particular, sphingosine-1-phosphate is involved in proliferation, differentiation and apoptosis. Sphingosine-1-phosphate can act both extracellularly through endothelial-differentiating gene (EDG) family G protein-coupled receptors and intracellularly through direct interactions with target proteins. The importance of sphingolipid signalling in cardiovascular development has been reinforced by recent reports implicating EDG receptors in the regulation of embryonic cardiac and vascular morphogenesis. Received 16 May 2001; received after revision 29 June 2001; accepted 3 July 2001     

Leptin signaling and circuits in puberty and fertility

Leptin is an adipocyte-derived hormone involved in a myriad of physiological process, including the control of energy balance and several neuroendocrine axes. Leptin-deficient mice and humans are obese, diabetic, and display a series of neuroendocrine and autonomic abnormalities. These individuals are infertile due to a lack of appropriate pubertal development and inadequate synthesis and secretion of gonadotropins and gonadal steroids. Leptin receptors are expressed in many organs and tissues, including those related to the control of reproductive physiology (e.g., the hypothalamus, pituitary gland, and gonads). In the last decade, it has become clear that leptin receptors located in the brain are major players in most leptin actions, including reproduction. Moreover, the recent development of molecular techniques for brain mapping and the use of genetically modified mouse models have generated crucial new findings for understanding leptin physiology and the metabolic influences on reproductive health. In the present review, we will highlight the new advances in the field, discuss the apparent contradictions, and underline the relevance of this complex physiological system to human health. We will focus our review on the hypothalamic circuitry and potential signaling pathways relevant to leptin’s effects in reproductive control, which have been identified with the use of cutting-edge technologies of molecular mapping and conditional knockouts.     

Nuclear calcium signalling

The topic of nuclear Ca2+ signalling is beset by discrepant observations of substantial nuclear/cytoplasmic gradients. The reasons why some labs have recorded such gradients, whilst other workers see equilibration of Ca2+(cyt) and Ca2+(nuc) using the same cells and techniques, is unexplained. Furthermore, how such gradients could arise across the NE that possesses many highly-conductive NPCs is a mystery. Although nuclei may have the capacity to be autonomous signalling entities, with functional Ca2+ release channels and an inositide cycle, the balance of evidence suggests that Ca2+ release on the inner NE does not occur during physiological stimulation. Our work suggests that elementary Ca2+ release events originating in the cytoplasm can give rise to Ca2+ signals without causing elevation of the bulk cytoplasm. Clearly, the many Ca2+ signalling mechanisms that may impinge on Ca2+(nuc) will remain a topic of controversy and debate for some time.