Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.3 (phospholipase C)
18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The parathyroid cell detects changes in the extracellular ionized calcium concentration (Ca2 + o) with exquisite sensitivity, but the mechanisms through which it senses Ca2 + o have remained obscure. Recently, we isolated a cDNA encoding a Ca2 + o-sensing receptor from bovine parathyroid using expression cloning in Xenopus laevis oocytes. The expressed receptor stimulates phospholipase C and has a pharmacological profile almost identical to that of the native receptor. Furthermore, its deduced amino acid sequence confirms that it belongs to the superfamily of G-protein-coupled receptors. Receptor transcripts are present in parathyroid and other tissues sensing Ca2 + o (e.g., kidney and thyroidal C-cells) as well as those not known to be involved in Ca2+ homeostasis (viz., in the brain). We have also shown that mutations in the receptor cause three inherited disorders of calcium metabolism: Familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT) result from inactivating mutations, when present in the heterozygous and homozygous states, respectively, whereas an autosomal dominant form of hypocalcemia is due to an activating mutation. Thus this Ca2 + o-sensing receptor permits Ca2+o to act as an extracellular, first messenger in addition to its better known role as an intracellular second messenger.
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PMID:The cloning of extracellular Ca(2+)-sensing receptors from parathyroid and kidney: molecular mechanisms of extracellular Ca(2+)-sensing. 760 78

The ability of the parathyroid cell to sense minute fluctuations in the extracellular ionized calcium concentration (Ca2+ o) is essential for maintaining mineral ion homeostasis. However, the mechanism(s) through which the parathyroid cell and other cells recognize and respond to changes in Ca2+ o has remained unclear. We recently isolated a cDNA encoding a Ca2+ o-sensing receptor from bovine parathyroid using expression cloning in Xenopus laevis oocytes. The receptor shows pharmacologic properties that are almost identical to those of the receptor on the parathyroid cell and, like the latter, stimulates phospholipase C in a G-protein-dependent manner. The amino acid sequence of the cloned receptor deduced from this cDNA predicts a protein with a molecular mass of 121 kd, which has three principal structural domains. The first is a 613 amino acid, putatively extracellular amino terminus which has several regions rich in acidic amino acids that may potentially be involved in binding Ca2+ and other polycationic agonists. The second comprises seven membrane-spanning segments that are characteristic of the superfamily of G-protein-coupled receptors, and the third is a 222 amino acid cytoplasmic tail. Transcripts for this Ca2+ o-sensing receptor are present in the parathyroid as well as in the kidney, thyroid, and brain. We next investigated the hypercalcemic disorders, familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism, as possible examples of inherited abnormalities in this Ca2+ o-sensing receptor, since both disorders show abnormal Ca2+ o-sensing and/or handling in the kidney and parathyroid.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Sensing of extracellular Ca2+ by parathyroid and kidney cells: cloning and characterization of an extracellular Ca(2+)-sensing receptor. 787 34

The current understanding of the cellular mode of action of PTH has undergone deep changes during the last decade and the major acquisitions can be summarized as follows. First, results from biochemical and cell biology studies suggest the existence of at least two receptor types coupled to two distinct intracellular signaling pathways by G proteins: the phospholipase C-calcium-protein kinase C pathway would be coupled to high-affinity receptors, whereas the adenylate cyclase-cAMP-protein kinase A pathway would be coupled to low-affinity receptors. Until now, only one type of PTH receptor has been identified at the molecular level. It is very likely that additional PTH receptor types will be evidenced. Second, both PTH receptor-coupled transduction pathways are involved in the inhibitory effect of the hormone on the activity of two transport systems of the apical membrane of proximal tubular cells: Na-Pi cotransport and Na-H exchanger. These effects are the cellular basis for PTH inhibition of Pi and bicarbonate reabsorption. Which proteins are the targets of the different protein kinases remains to be established. Concerning the other effects of PTH on the proximal tubule (stimulation of neoglucogenesis and of calcitriol synthesis, and Na, K-ATPase inhibition), protein kinase C seems to play a major role. Third, in Henle's loop, PTH stimulates reabsorption of divalent cations through a dual effect under the dependence of protein kinase A, i.e., enhanced epithelial potential difference and opening of paracellular pathway. Finally, stimulation of distal calcium reabsorption results from multiple events: membrane insertion of apical calcium channels, opening of basolateral chloride channels resulting in cellular hyperpolarization, and modulation of Ca-ATPase. Again, while it is commonly acknowledged that both transduction systems are involved, their precise molecular targets remain to be identified (Table 1). The elucidation of the cellular mode of action of PTH, some examples of which have been reviewed, holds major interest far beyond the field of cell or organ physiology. It is the basis for understanding and, ultimately, for comprehensive treatment of genetic diseases characterized by functional abnormalities of molecules involved in the cascade of events leading to the effect of PTH on its cellular targets (hormone receptors, G proteins, and kinases). The second perspective is pharmacologic: molecular and structural identification of PTH-receptor interactions will be a prelude to design and synthesis of new selective, nonpeptidic hormonal analogs and antagonists that are easier to handle. The high incidence and severity of secondary hyperparathyroidism during chronic renal failure highlights the importance of this research.
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PMID:Cellular mode of action of parathyroid hormone. 815 58

Parathyroid cells recognize and respond to (i.e., "sense") minute perturbations in the extracellular ionized calcium concentration (Ca2+o), but the mechanisms underlying this process have remained obscure. Recently, we employed expression cloning in Xenopus laevis oocytes to isolate a cDNA coding for a Ca2+o-sensing receptor from bovine parathyroid. Like the native receptor, the cloned Ca2+o-sensing receptor stimulates phospholipase C (PLC) in a G-protein-dependent manner with a nearly identical pharmacological profile. Its deduced amino acid sequence confirms that it is a member of the superfamily of G-protein-coupled receptors (GPR). Transcripts for the receptor are expressed in parathyroid and other tissues that sense Ca2+o (viz., kidney and thyroidal C-cells) as well as those that have no known role in extracellular Ca2+ homeostasis, such as the brain. The availability of the cDNA clone for the Ca2+o-sensing receptor made it possible to test the hypothesis that mutations in the gene encoding the human homolog of the receptor cause inherited disorders of mineral ion metabolism. Familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT) are, in fact, caused by mutations that reduce the activity of the receptor when they are present in the heterozygous and homozygous states, respectively. In contrast, we have subsequently discovered a family in which a form of autosomal dominant hypocalcemia results from an activating mutation in the receptor gene. The Ca2+-sensing receptor, therefore, permits Ca2+o to play a "hormonelike" role as an extracellular first messenger in addition to its well described role as an important intracellular second messenger.
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PMID:Cloning and functional characterization of extracellular Ca(2+)-sensing receptors from parathyroid and kidney. 857 1

Changes in the extracellular calcium concentration [Ca2+]o modulate several aspects of renal function through unknown mechanism(s). cDNA encoding a Ca2+o-sensing receptor from bovine parathyroid and rat kidney that appears to mediate several of the known effects of Ca2+o on parathyroid and renal function were recently isolated. The expressed receptor activates phospholipase C, showing a pharmacologic profile very similar to that of the native receptor. Its deduced amino acid sequence identifies it as a member of the superfamily of G protein-coupled receptors. The physiologic relevance of the receptor has been established by the demonstration that mutations in it cause three inherited diseases of calcium metabolism. Two hypercalcemic disorders, familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism, result from inactivating mutations when present in the heterozygous and homozygous states, respectively. An activating mutation, in contrast, causes an autosomal dominant form of hypocalcemia. In the kidney, the receptor is expressed most abundantly in the thick ascending limb, where it likely modulates sodium chloride, calcium, and magnesium reabsorption and, perhaps, urinary concentrating ability. Studies are currently underway to determine whether it also mediates the effects of Ca2+o on other parameters of kidney function, such as RBF, glomerular filtration, renin secretion, and vitamin D metabolism. Thus, this Ca2+o-sensing receptor permits extracellular calcium ions to act not only as an intracellular second messenger but also in a "hormone-like" role as an extracellular first messenger.
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PMID:A cloned Ca(2+)-sensing receptor: a mediator of direct effects of extracellular Ca2+ on renal function? 874 77

The recent cloning of an extracellular calcium (Ca2+o)-sensing receptor (CaR) from the parathyroid gland and the kidney has provided novel insights into the mechanisms that underlie the direct actions of Ca2+o on various cells. The receptor is a member of the superfamily of G protein-coupled receptors, activating phospholipase C (PLC) and probably also inhibiting adenylate cyclase in target tissues. In the parathyroid gland it is a key mediator of the inhibition by high Ca2+o of parathyroid hormone (PTH) secretion and, perhaps, PTH gene expression and parathyroid cellular proliferation. It also appears to represent the major mechanism through which Ca2+o stimulates the secretion of calcitonin from the thyroidal C-cells. In the kidney, the CaR directly inhibits tubular reabsorption of calcium and magnesium in the thick ascending limb, and may be responsible for the long-recognized, but poorly understood inhibition of urinary concentrating ability by hypercalcemia. The demonstration that activating and inactivating mutations of the CaR, respectively, are the proximate causes of the inherited hypocalcemic disorder, autosomal dominant hypocalcemia (ADH) and the hypercalcemic diseases, familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT), has provided additional strong support for the physiologic importance of the CaR in human mineral ion homeostasis. Therefore, when Ca2+o acts through its own G protein-coupled cell surface receptor, it acts as an extracellular first messenger in addition to serving its better recognized role as a key intracellular second messenger.
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PMID:The First Annual Bayard D. Catherwood Memorial Lecture. Ca2+-receptor-mediated regulation of parathyroid and renal function. 878 75

The discovery of the calcium-sensing receptor (CaR), a G protein-coupled receptor, has led to the elucidation of the pivotal roles of the CaR in systemic calcium homeostasis. The receptor is situated on the chief cells of the parathyroid glands, where it senses the extracellular Ca2+ concentration and in turn alters the rate of secretion of parathyroid hormone (PTH). The intracellular signal pathways to which the CaR couples include, but are not limited to, phospholipase C (PLC), and mitogen-activated protein kinases. The receptor is widely expressed in various tissues and likely serves important cellular functions beyond that of maintaining systemic calcium homeostasis. Functionally important mutations in the receptor have been found to cause disorders in calcium homeostasis due both to changes in the set point for PTH secretion and to the control of renal calcium excretion. These mutations cause hypercalcemia when the mutation inactivates the receptor and cause hypocalcemia when the mutation activates the receptor. Recent studies have revealed the presence of circulating autoantibodies to the calcium-sensing receptor in humans, with the clinical presentation the same as that for diseases caused by mutations in the CaR. In renal secondary hyperparathyroidism, a drug that stimulates the receptor (calcimimetic) shows great promise as a medical treatment for this condition.
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PMID:The calcium-sensing receptor in human disease. 1270 51

An excess of free intracellular calcium can reduce the efficiency of insulin-mediated glucose transport by blocking the dephosphorylation of GLUT-4. Classical isoforms of protein kinase C (PKC) can interfere with insulin signalling via serine phosphorylation of IRS-1 and the insulin receptor. Parathyroid hormone (PTH), by activating phospholipase C-beta in adipocytes, can promote a sustained increase in intracellular free calcium in these cells, while also activating classical PKCs. This may rationalize the fact that insulin resistance is a typical feature of hyperparathyroidism, as well as epidemiological evidence that regular ingestion of dairy products or of ethanol--which down-regulates PTH secretion--reduces risk for insulin resistance syndrome and diabetes. Alpha-1 adrenergic receptors of adipocytes--like PTH receptors--also activate phospholipase C-beta, and thus have an effect analogous to PTH on intracellular free calcium and PKC activity in adipocytes. This suggests that, via activation of alpha-1 adrenergic receptors, increased sympathetic activity in adipose tissue may promote insulin resistance syndrome. In fact, measures which provoke increased sympathetic output--such as diuretic use and severe salt restriction--are known to compromise insulin sensitivity, whereas alpha-1 antagonist drugs, as well as drugs that act centrally to suppress sympathetic activity, typically have a favorable effect on insulin function. When insulin resistance syndrome is associated with elevated sympathetic activity--for example, in hypertensives who are obese or on diuretic therapy--measures which down-regulate sympathetic activity, or, more specifically, alpha-1 adrenergic activity, may be warranted. These include centrally acting imidazoline analogs (moxonidine, rilmenidine) and alpha-1 antagonists (doxazosin, prazosin). Taurine and high-dose pyridoxine may represent practical nutritional strategies for moderating elevated sympathetic activity, and exercise training and low-insulin-response diets may be useful in this regard as well.
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PMID:Elevated sympathetic activity may promote insulin resistance syndrome by activating alpha-1 adrenergic receptors on adipocytes. 1508 16

The discovery of a G protein-coupled, calcium-sensing receptor (CaR) a decade ago and of diseases caused by CaR mutations provided unquestionable evidence of the CaR's critical role in the maintenance of systemic calcium homeostasis. On the cell membrane of the chief cells of the parathyroid glands, the CaR "senses" the extracellular calcium concentration and, subsequently, alters the release of parathyroid hormone (PTH). The CaR is likewise functionally expressed in bone, kidney, and gut--the three major calcium-translocating organs involved in calcium homeostasis. Intracellular signal pathways to which the CaR couples via its associated G proteins include phospholipase C (PLC), protein kinase B (AKT); and mitogen-activated protein kinases (MAPKs). The receptor is widely expressed in various tissues and regulates important cellular functions in addition to its role in maintaining systemic calcium homeostasis, i.e., protection against apoptosis, cellular proliferation, and membrane voltage. Functionally significant mutations in the receptor have been shown to induce diseases of calcium homeostasis owing to changes in the set point for calcium-regulated PTH release as well as alterations in the renal handling of calcium. Gain-of-function mutations cause hypocalcemia, whereas loss-of-function mutations produce hypercalcemia. Recent studies have shown that the latter clinical presentation can also be caused by inactivating autoantibodies directed against the CaR Newly discovered type II allosteric activators of the CaR have been found to be effective as a medical treatment for renal secondary hyperparathyroidism.
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PMID:The calcium-sensing receptor in normal physiology and pathophysiology: a review. 1569 70

Inward rectifier K⁺ channels are important for maintaining normal electrical function in many cell types. The proper function of these channels requires the presence of membrane phosphoinositide 4,5-bisphosphate (PIP₂). Stimulation of the Ca²⁺-sensing receptor CaR, a pleiotropic G protein-coupled receptor, activates both G_q/11, which decreases PIP₂, and phosphatidylinositol 4-kinase (PI-4-K), which, conversely, increases PIP₂. How membrane PIP₂ levels are regulated by CaR activation and whether these changes modulate inward rectifier K⁺ are unknown. In this study, we found that activation of CaR by the allosteric agonist, NPSR568, increased inward rectifier K⁺ current (I _K1) in guinea pig ventricular myocytes and currents mediated by Kir2.1 channels exogenously expressed in HEK293T cells with a similar sensitivity. Moreover, using the fluorescent PIP₂ reporter tubby-R332H-cYFP to monitor PIP₂ levels, we found that CaR activation in HEK293T cells increased membrane PIP₂ concentrations. Pharmacological studies showed that both phospholipase C (PLC) and PI-4-K are activated by CaR stimulation with the latter played a dominant role in regulating membrane PIP₂ and, thus, Kir currents. These results provide the first direct evidence that CaR activation upregulates currents through inward rectifier K⁺ channels by accelerating PIP₂ synthesis. The regulation of I _K1 plays a critical role in the stability of the electrical properties of many excitable cells, including cardiac myocytes and neurons. Further, synthetic allosteric modulators that increase CaR activity have been used to treat hyperparathyroidism, and negative CaR modulators are of potential importance in the treatment of osteoporosis. Thus, our results provide further insight into the roles played by CaR in the cardiovascular system and are potentially valuable for heart disease treatment and drug safety.
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PMID:Activation of the Ca²⁺-sensing receptors increases currents through inward rectifier K⁺ channels via activation of phosphatidylinositol 4-kinase. 2783 49


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