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An integrated approach using the tools of molecular genetics 1pack slip inn sale wholesale herbs, molecular biology discount slip inn online mastercard herbals essences, and physiology has been applied in the 1990s to identify defects in transporters buy slip inn 1pack visa herbals for horses, channels, receptors, and enzymes involved in epithelial transport. These investigations have added substantial insight into the molecular mechanisms involved in renal solute transport and the molecular pathogenesis of inherited renal tubular disorders. This chapter focuses on the inherited renal tubular disorders, highlights their molecular defects, and discusses models to explain their under- lying pathogenesis. For m any of Inherited disorder Transmission mode Defective protein these disorders, the identification of the disease-susceptibility gene and its associated Renal glucosuria? AR, AD Sodium-glucose transporter 2 defective protein product has begun to pro- Glucose-galactose malabsorption syndrome AR Sodium-glucose transporter 1 vide insight into the m olecular pathogenesis Acidic aminoaciduria AR Sodium-potassium–dependent of the disorder. Blue diaper syndrome AR Kidney-specific tryptophan transporter Neutral aminoacidurias: AR? Methioninuria Iminoglycinuria Glycinuria Hereditary hypophosphatemic rickets AR? Urate transporter AD— autosomal dominant; AR— autosomal recessive; ClC-K2— renal chloride channel; NCCT— thiazide-sensitive cotransporter; NKCC2— bumetanide-sensitive cotransporter; ROMK— inwardly rectified. Under Tmax norm al physiologic conditions, filtered glucose is alm ost entirely Observed curve reabsorbed in the proxim al tubule by way of two distinct sodium - coupled glucose transport system s. In the S1 and S2 segm ents, bulk Threshold reabsorption of glucose load occurs by way of a kidney-specific 200 high-capacity transporter, the sodium -glucose transporter-2 (SGLT2). The residual glucose is rem oved from the filtrate in the S3 seg- m ent by way of the high-affinity sodium -glucose transporter-1 (SGLT1). This transporter also is present in the sm all intestine. As are all m em brane transport system s, glucose transporters are saturable. The top panel shows that increasing the glucose concen- 0 tration in the tubular fluid accelerates the transport rate of the 0 200 400 600 glucose transporters until a m axim al rate is achieved. The term 400 threshold applies to the point that glucose first appears in the urine. The m axim al overall rate of glucose transport by the proxi- Normal m al tubule SGLT1 and SGLT2 is term ed the Tm ax. Glucose is detected in urine either when the filtered load is increased (as in Type B renal glucosuria diabetes m ellitus) or, as shown in the bottom panel, when a defect occurs in tubular reabsorption (as in renal glucosuria). Kinetic 200 studies have dem onstrated two types of glucosuria caused by either reduced m axim al transport velocity (type A) or reduced affinity of Type A renal glucosuria the transporter for glucose (type B). M utations in the gene encoding SGLT1 cause glucose-galactose m alabsorption syndrom e, a severe autosom al recessive intestinal disorder associated with 0 m ild renal glucosuria (type B). Defects in SGLT2 result in a com - 0 200 400 600 paratively m ore severe renal glucosuria (type A). H owever, this dis- Filtered glucose load, mg/min 1. Am ong m em bers of the basolateral glu- cose transporter (GLUT) fam ily, only GLUT1 and GLUT2 are rele- vant to renal physiology. Clinical disorders associated with m utations in the genes encoding these transporters have yet to be described. FIGURE 12-3 O ver 95% of the filtered am ino acid load is norm ally reabsorbed in Cystine actually is a neutral am ino acid that shares a com m on the proxim al tubule. The term am inoaciduria is applied when m ore carrier with the dibasic am ino acids lysine, arginine, and ornithine. Am inoaciduria The transport of all four am ino acids is disrupted in cystinuria. The can occur in the context of m etabolic defects, which elevate plasm a rarer disorder, lysinuric protein intolerance, results from defects in am ino acid concentrations and thus increase the glom erular filtered the basolateral transport of dibasic am ino acids but not cystine. In addition, am inoaciduria can arise from genetic defects in consequent hyperam m onem ia. Three distinct groups of inherited am inoacidurias are distin- H artnup disease, blue diaper syndrom e, m ethioninuria, im inogly- guished based on the net charge of the target am ino acids at neutral cinuria, and glycinuria. Several neutral am ino acid transporters pH : acidic (negative charge), basic (positive charge), and neutral have been cloned and characterized. H artnup disease involves a neutral am ino acid transport system Acidic am inoaciduria involves the transport of glutam ate and in both the kidney and intestine, whereas blue diaper syndrom e aspartate and results from a defect in the high-affinity sodium - involves a kidney-specific tryptophan transporter. M ethioninuria potassium –dependent glutam ate transporter. It is a clinically appears to involve a separate m ethionine transport system in the benign disorder. Case reports describe seizures, m ental retardation, Four syndrom es caused by defects in the transport of basic and episodic hyperventilation in affected patients. The patho- am ino acids or cystine have been described: cystinuria, lysinuric physiologic basis for this phenotype is unclear. Im inoglycinuria protein intolerance, isolated cystinuria, and isolated lysinuria. Differences in the urinary Category Phenotype Intestinal transport defect excretion of cystine in obligate heterozygotes and intestinal amino acid transport studies in I hom ozygotes have provided the basis for Heterozygote No abnormality defining three distinct phenotypes of cystin- Homozygote Cystinuria, basic aminoaciduria, cystine stones Cystinine, basic amino acids uria. Genetic studies have identified II m utations in the gene (SCL3A1) encoding a Heterozygote Excess excretion of cystine and basic amino acids Homozygote Cystinuria, basic aminoaciduria, cystine stones Basic amino acids only high-affinity transporter for cystine and the III dibasic am ino acids in patients with type I Heterozygote Excess excretion of cystine and basic amino acids cystinuria [10,11]. In patients with type III Homozygote Cystinuria, basic aminoaciduria, cystine stones None cystinuria, SCL3A1 was excluded as the disease-causing gene. A second cystin- uria-susceptibility gene recently has been From Morris and Ives; with permission. Excessive urinary excretion of cystine (250 to 1000 mg/d of cystine/g of creatinine) coupled with its poor solubility in urine causes cystine precipitation with the formation of characteris- tic urinary crystals and urinary tract calculi. Stone formation often causes urinary tract obstruction and the associated problems of renal colic, infection, and even renal failure. The treatment objective is to reduce urinary cystine concentration or to increase its solubility. High fluid intake (to keep the urinary cystine concentration below the solubility threshold of 250 mg/L) and urinary alkalization are the mainstays of therapy. For those patients refractory to conservative management, treatment with sulfhydryl-containing drugs, such as D-penicillamine, mercaptopropionylglycine, and even captopril can be efficacious [14,15]. These disorders include X-linked hypo- osteomalacia in adults. These disorders can be distinguished on phosphatemic rickets (HYP), hereditary hypophosphatemic rickets the basis of the renal hormonal response to hypophosphatemia, the with hypercalciuria (HHRH), hypophosphatemic bone disease (HBD), biochemical profile, and responsiveness to therapy. In addition, the autosomal dominant hypophosphatemic rickets (ADHR), autosomal rare disorder XLRH is associated with nephrolithiasis. The clinical recessive hypophosphatemic rickets (ARHR), and X-linked recessive features of the two most common disorders HYP and HHRH are hypophosphatemic rickets (XLRH). W hereas both disorders have defects in renal Pi two com m on features: persistent hypophosphatem ia caused by reabsorption, the renal hormonal response to hypophosphatemia is decreased renal tubular phosphate (Pi) reabsorption (expressed as im paired in H YP but not in H H RH.
Although relatively little is dowment Fund for Neuroscience 1pack slip inn otc herbals teas for the lungs, and the Human Frontier known about the functional roles of these phenomena discount slip inn on line herbs definition, such Science Program 1pack slip inn with mastercard herbals solutions. Thanks to Roger Nicoll, Steven changes in synaptic function and structure remain the lead- Siegelbaum, Christian Luscher¨ and Dominique Muller, Chapter 11: Synaptic Plasticity 155 with whom I have written previous reviews that provided amino acid-induced excitations of rat hippocampal CA1 neu- much of the material for the present chapter. Intracellular injections of EGTA REFERENCES block induction of hippocampal long-term potentiation. Short-term synaptic LTD by postsynaptic [Ca2 ]i elevation. J Neurophysiol 1999;81: plasticity is altered in mice lacking synapsin I. 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OLSEN GABA IS THE MAJOR INHIBITORY doxal phosphate and the subcellular localization (7). GABA NEUROTRANSMITTER IN THE NERVOUS was shown to be released from electrically stimulated inhibi- SYSTEM tory nerve cells (8), and a mechanism of rapid removal from the synaptic release site was demonstrated by identification Several amino acids are found in high concentrations in of high-affinity transporter proteins (9,10). The application brain, and some have been established as neurotransmitters. Glycine is a secondary rapid inhibitory neurotransmitter, especially in the spinal cord (1,2).
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