Small intestinal ion transport

Kiela, Pawel R.

doi:10.1097/mog.0b013e32834e7bc3

Cited by 26 publications

(22 citation statements)

References 26 publications

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“…Water passively follows the ion movement paracellularly, through the tight junctions, or transcellularly, through the cell membrane, in order to avoid the buildup of osmotic gradients. (18) NHE3 mutations in classical CSD.…”

Section: Congenital Sodium Diarrhea: Etiology and Pathogenesismentioning

confidence: 99%

Congenital Sodium Diarrhea

Janecke

Heinz‐Erian

Müller

2016

J. pediatr. gastroenterol. nutr.

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Congenital diarrheal disorders (CDDs) represent a group of challenging clinical conditions for pediatricians because of the severity of the presentation and the broad range of possible differential diagnoses. CDDs arise from alterations in the transport of nutrients and electrolytes across the intestinal mucosa, from enterocyte and enteroendocrine cell differentiation and/or polarization defects, and from the modulation of the intestinal immune response. Advances were made recently in deciphering the etiology and pathophysiology of one of these disorders, congenital sodium diarrhea (CSD). CSD refers to an intractable diarrhea of intrauterine onset with high fecal sodium loss. CSD is clinically and genetically heterogeneous. A syndromic form of CSD features choanal and intestinal atresias as well as recurrent corneal erosions. Small bowel histology frequently detects an epithelial "tufting" dysplasia. It is autosomal recessively inherited, and caused by SPINT2 mutations. The nonsyndromic form of CSD can be caused by dominant activating mutations in GUCY2C, encoding intestinal receptor guanylate cyclase C (GC-C), and by autosomal recessive SLC9A3 loss-of-function mutations. SLC9A3 encodes Na/H antiporter 3, the major intestinal brush border Na/H exchanger, and a downstream target of GC-C. A number of patients with GUCY2C and SLC9A3 mutations developed inflammatory bowel disease. Both the number of recognized CDD forms as well as the number of underlying disease genes are gradually increasing. Knowledge of these CDD genes enables noninvasive, next-generation gene panel-based testing to facilitate an early diagnosis in CDD. Primary Na/H antiporter 3 and GC-C malfunction is implicated as a predisposition for inflammatory bowel disease in subset of patients.

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Section: Congenital Sodium Diarrhea: Etiology and Pathogenesismentioning

confidence: 99%

Congenital Sodium Diarrhea

Janecke

Heinz‐Erian

Müller

2016

J. pediatr. gastroenterol. nutr.

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“…DRA is also part of the anion secretory process, accounting for a component of cAMP-stimulated intestinal HCO 3 - secretion. 1-4…”

Section: Introductionmentioning

confidence: 99%

cAMP stimulates SLC26A3 activity in human colon by a CFTR-dependent mechanism that does not require CFTR activity

Tse

Yin

Singh

et al. 2018

Preprint

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“…Maintenance of the subcellular architecture by NHERF proteins is critical for salient cell functions, for example in the kidney, small intestine, and other organs, where they interact with transporters, ion channels, signaling proteins, transcription factors, enzymes, G protein-coupled receptors (GPCRs), and tyrosine kinase receptors (20)(21)(22)(23)(24). NHERF proteins regulate phosphate transport in proximal tubule cells (25), are involved in ion transport in the small intestine (26), and regulate the activity of the glutamate transporter GLAST and of the metabolic glutamate receptor mGlu5 in astrocytes (27,28). Moreover, they play a role in cell growth and cancer (29)(30)(31).…”

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confidence: 99%

Dynamic NHERF interaction with TRPC4/5 proteins is required for channel gating by diacylglycerol

Storch

Forst

Pardatscher

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

122

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The activation mechanism of the classical transient receptor potential channels TRPC4 and -5 via the G q/11 protein-phospholipase C (PLC) signaling pathway has remained elusive so far. In contrast to all other TRPC channels, the PLC product diacylglycerol (DAG) is not sufficient for channel activation, whereas TRPC4/5 channel activity is potentiated by phosphatidylinositol 4,5-bisphosphate (PIP 2 ) depletion. As a characteristic structural feature, TRPC4/5 channels contain a C-terminal PDZ-binding motif allowing for binding of the scaffolding proteins Na+ exchanger regulatory factor (NHERF) 1 and 2. PKC inhibition or the exchange of threonine for alanine in the C-terminal PDZ-binding motif conferred DAG sensitivity to the channel. Altogether, we present a DAG-mediated activation mechanism for TRPC4/5 channels tightly regulated by NHERF1/2 interaction. PIP 2 depletion evokes a C-terminal conformational change of TRPC5 proteins leading to dynamic dissociation of NHERF1/2 from the C terminus of TRPC5 as a prerequisite for DAG sensitivity. We show that NHERF proteins are direct regulators of ion channel activity and that DAG sensitivity is a distinctive hallmark of TRPC channels.and -5 channels are members of the classical transient receptor potential cation (TRPC) family of nonselective, calcium permeable receptor-operated cation channels. They are widely expressed in many tissues, including brain, kidney, and the vascular system. High expression levels are found in the central nervous system where TRPC4 and -5 are involved in amygdala function and fear-related behavior (1, 2), seizure, and excitotoxicity (3). Furthermore, TRPC5 channels are implicated in neuronal depolarization and bursting during epiletiform seizures (4) and regulate hippocampal neurite length and growth cone morphology (5). In the kidney, TRPC5 channels are proposed to be protective against renal failure (6). TRPC channels are usually activated by G q/11 proteincoupled receptors via phospholipase C (PLC) activation resulting in cleavage of phosphatidylinositol-3,4-bisphosphate (PIP 2 ) into the second messengers inositol-1,4,5-trisphosphate (IP 3 ) and diacylglycerol (DAG). DAG is known to activate TRPC2, -3, -6, and -7 (7-9) channels, whereas TRPC4 and -5 are supposed to be insensitive to the PLC product DAG (8) and are even inhibited by DAG or its membrane-permeable analog 1-oleoyl-2-acetyl-sn-glycerol (OAG) (10). DAG-mediated TRPC5 channel inhibition was shown to be PKC dependent (10). Furthermore, TRPC4 and -5 channels can be activated by depleting PIP 2 (11, 12), contrary to TRPC6 and -7 channels, which are inhibited by PIP 2 depletion (13). However, there are first hints to show that endogenously expressed TRPC5 channels might be DAG sensitive (14) but mechanistic insight is lacking so far.A noteworthy structural difference between TRPC4 and -5 and the established DAG-sensitive TRPC3, -6, and -7 channels is the PDZbinding motif VTTLR in the C termini of TRPC4 and -5 channels (15-17) as a structural basis of the interaction with Na + /H + e...

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Small intestinal ion transport

Cited by 26 publications

References 26 publications

Congenital Sodium Diarrhea

Congenital Sodium Diarrhea

cAMP stimulates SLC26A3 activity in human colon by a CFTR-dependent mechanism that does not require CFTR activity

Dynamic NHERF interaction with TRPC4/5 proteins is required for channel gating by diacylglycerol

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