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Aquaporin-2: new mutations responsible for autosomal-recessive nephrogenic diabetes insipidus-update and epidemiology.

Bichet DG, El Tarazi A, Matar J, Lussier Y, Arthus MF, Lonergan M, Bockenhauer D, Bissonnette P - Clin Kidney J (2012)

Bottom Line: Patients with polyhydramnios, profound polyuria, hyponatremia, hypochloremia, metabolic alkalosis and sensorineural deafness were found to bear BSND mutations.These clinical phenotypes demonstrate the critical importance of the proteins ROMK, NKCC2 and Barttin to transfer NaCl in the medullary interstitium and thereby to generate, together with urea, a hypertonic milieu.This editorial describes two new developments: (i) the genomic information provided by the sequencing of the AQP2 gene is key to the routine care of these patients, and, as in other genetic diseases, reduces health costs and provides psychological benefits to patients and families and (ii) the expression of AQP2 mutants in Xenopus oocytes and in polarized renal tubular cells recapitulates the clinical phenotypes and reveals a continuum from severe loss of function with urinary osmolalities <150 mOsm/kg H2O to milder defects with urine osmolalities >200 mOsm/kg H2O.

View Article: PubMed Central - PubMed

Affiliation: Groupe d'Étude des Protéines Membranaires (GÉPROM), Département de Physiologie, Université de Montréal, Montréal, Québec, Canada ; Centre de Recherche, Hôpital du Sacré-Cœur de Montréal, Montréal, Québec, Canada.

ABSTRACT
It is clinically useful to distinguish between two types of hereditary nephrogenic diabetes insipidus (NDI): a 'pure' type characterized by loss of water only and a complex type characterized by loss of water and ions. Patients with congenital NDI bearing mutations in the vasopressin 2 receptor gene, AVPR2, or in the aquaporin-2 gene, AQP2, have a pure NDI phenotype with loss of water but normal conservation of sodium, potassium, chloride and calcium. Patients with hereditary hypokalemic salt-losing tubulopathies have a complex phenotype with loss of water and ions. They have polyhydramnios, hypercalciuria and hypo- or isosthenuria and were found to bear KCNJ1 (ROMK) and SLC12A1 (NKCC2) mutations. Patients with polyhydramnios, profound polyuria, hyponatremia, hypochloremia, metabolic alkalosis and sensorineural deafness were found to bear BSND mutations. These clinical phenotypes demonstrate the critical importance of the proteins ROMK, NKCC2 and Barttin to transfer NaCl in the medullary interstitium and thereby to generate, together with urea, a hypertonic milieu. This editorial describes two new developments: (i) the genomic information provided by the sequencing of the AQP2 gene is key to the routine care of these patients, and, as in other genetic diseases, reduces health costs and provides psychological benefits to patients and families and (ii) the expression of AQP2 mutants in Xenopus oocytes and in polarized renal tubular cells recapitulates the clinical phenotypes and reveals a continuum from severe loss of function with urinary osmolalities <150 mOsm/kg H2O to milder defects with urine osmolalities >200 mOsm/kg H2O.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of the effect of vasopressin (AVP) to increase water permeability in the principal cells of the collecting duct. AVP is bound to the V2 receptor (a G-protein-linked receptor) on the basolateral membrane. The basic process of G-protein-coupled receptor signaling consists of three steps: a hepta-helical receptor that detects a ligand (in this case, AVP) in the extracellular milieu, a G-protein (Gαs) that dissociates into a subunits bound to guanosine triphosphate and bg subunits after interaction with the ligand-bound receptor and an effector (in this case, adenylyl cyclase) that interacts with dissociated G-protein subunits to generate small molecule second messengers. AVP activates adenylyl cyclase, increasing the intracellular concentration of cAMP. The topology of adenylyl cyclase is characterized by two tandem repeats of six hydrophobic transmembrane domains separated by a large cytoplasmic loop and terminates in a large intracellular tail. The dimeric structure (C1 and C2) of the catalytic domains is represented. Conversion of adenosine triphosphate (ATP) to cAMP takes place at the dimer interface. Two aspartate residues (in C1) coordinate two metal co-factors (Mg2+ or Mn2+ represented here as two small black circles), which enable the catalytic function of the enzyme. Adenosine is shown as an open circle and the three phosphate groups (ATP) are shown as smaller open circles. PKA is the target of the generated cAMP. The binding of cAMP to the regulatory subunits of PKA induces a conformational change, causing these subunits to dissociate from the catalytic subunits. These activated subunits (C) as shown here are anchored to an aquaporin-2 (AQP2)-containing endocytic vesicle via an A-kinase-anchoring protein. The local concentration and distribution of the cAMP gradient are limited by phosphodiesterases (PDEs). Cytoplasmic vesicles carrying the water channels (represented as homotetrameric complexes) are fused to the luminal membrane in response to AVP, thereby increasing the water permeability of this membrane. The dissociation of the A-kinase-anchoring protein from the endocytic vesicle is not represented. Microtubules and actin filaments are necessary for vesicle movement toward the membrane. When AVP is not available, AQP2 water channels are retrieved by an endocytic process, and water permeability returns to its original low rate. Aquaporin-3 (AQP3) and aquaporin-4 (AQP4) water channels are expressed constitutively at the basolateral membrane.
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fig5: Schematic representation of the effect of vasopressin (AVP) to increase water permeability in the principal cells of the collecting duct. AVP is bound to the V2 receptor (a G-protein-linked receptor) on the basolateral membrane. The basic process of G-protein-coupled receptor signaling consists of three steps: a hepta-helical receptor that detects a ligand (in this case, AVP) in the extracellular milieu, a G-protein (Gαs) that dissociates into a subunits bound to guanosine triphosphate and bg subunits after interaction with the ligand-bound receptor and an effector (in this case, adenylyl cyclase) that interacts with dissociated G-protein subunits to generate small molecule second messengers. AVP activates adenylyl cyclase, increasing the intracellular concentration of cAMP. The topology of adenylyl cyclase is characterized by two tandem repeats of six hydrophobic transmembrane domains separated by a large cytoplasmic loop and terminates in a large intracellular tail. The dimeric structure (C1 and C2) of the catalytic domains is represented. Conversion of adenosine triphosphate (ATP) to cAMP takes place at the dimer interface. Two aspartate residues (in C1) coordinate two metal co-factors (Mg2+ or Mn2+ represented here as two small black circles), which enable the catalytic function of the enzyme. Adenosine is shown as an open circle and the three phosphate groups (ATP) are shown as smaller open circles. PKA is the target of the generated cAMP. The binding of cAMP to the regulatory subunits of PKA induces a conformational change, causing these subunits to dissociate from the catalytic subunits. These activated subunits (C) as shown here are anchored to an aquaporin-2 (AQP2)-containing endocytic vesicle via an A-kinase-anchoring protein. The local concentration and distribution of the cAMP gradient are limited by phosphodiesterases (PDEs). Cytoplasmic vesicles carrying the water channels (represented as homotetrameric complexes) are fused to the luminal membrane in response to AVP, thereby increasing the water permeability of this membrane. The dissociation of the A-kinase-anchoring protein from the endocytic vesicle is not represented. Microtubules and actin filaments are necessary for vesicle movement toward the membrane. When AVP is not available, AQP2 water channels are retrieved by an endocytic process, and water permeability returns to its original low rate. Aquaporin-3 (AQP3) and aquaporin-4 (AQP4) water channels are expressed constitutively at the basolateral membrane.

Mentions: The transfer of water across the principal cells of the collecting ducts is now known at such a detailed level that billions of molecules of water traversing the membrane can be represented; see useful teaching tools at http://www.mpibpc.gwdg.de/abteilungen/073/gallery.html and http://www.ks.uiuc.edu/research/aquaporins. The 2003 Nobel Prize in chemistry was awarded to Peter Agre and Roderick MacKinnon, who solved two complementary problems presented by the cell membrane: how does a cell let one type of ion through the lipid membrane to the exclusion of other ions? And how does it permeate water without ions? This contributed to creating momentum and renewed interest in basic discoveries related to the transport of water and indirectly to diabetes insipidus [57, 58]. The first step in the action of AVP (Synthetized by du Vigneaud, Nobel Prize in Chemistry 1955) [59] on water excretion is its binding to arginine vasopressin type 2 receptors (hereafter referred to as V2 receptors) on the basolateral membrane of the collecting duct cells (Figure 5). The human AVPR2 gene that codes for the V2 receptor is located in the chromosome region Xq28 and has three exons and two small introns [12, 60]. The sequence of the complementary DNA predicts a polypeptide of 371 amino acids with seven transmembrane, four extracellular and four cytoplasmic domains. The activation of the V2 receptor on renal collecting tubules stimulates adenylyl cyclase via the stimulatory G protein (Gs) (1994 Nobel Prize in Physiology and Medicine to Rodbell and Gilman for signal transduction and G-proteins) and promotes the cAMP-mediated incorporation of water channels into the luminal surface of these cells [61]. E. Sutherland and T. Rall isolated cAMP in 1956 and Sutherland was awarded the Nobel Prize in Physiology or Medicine in 1971 [62]. There are two ubiquitously expressed intracellular cAMP receptors: (i) the classical protein kinase A (PKA) that is a cAMP-dependent protein kinase and (ii) the recently discovered exchange protein directly activated by cAMP that is a cAMP-regulated guanine nucleotide exchange factor. Both these receptors contain an evolutionally conserved cAMP-binding domain that acts as a molecular switch for sensing intracellular cAMP levels to control diverse biological functions [63]. Several proteins participating in the control of cAMP-dependent AQP2 trafficking have been identified; for example, A-kinase-anchoring proteins tethering PKA to cellular compartments; phosphodiesterases regulating the local cAMP level; cytoskeletal components such as F-actin and microtubules; small GTPases of the Rho family controlling cytoskeletal dynamics; motor proteins transporting AQP2-bearing vesicles to and from the plasma membrane for exocytic insertion and endocytic retrieval and SNAREs inducing membrane fusions, hsc70, a chaperone important for endocytic retrieval. These processes are the molecular basis of the vasopressin-induced increase in the osmotic water permeability of the apical membrane of the collecting tubule [64–66].


Aquaporin-2: new mutations responsible for autosomal-recessive nephrogenic diabetes insipidus-update and epidemiology.

Bichet DG, El Tarazi A, Matar J, Lussier Y, Arthus MF, Lonergan M, Bockenhauer D, Bissonnette P - Clin Kidney J (2012)

Schematic representation of the effect of vasopressin (AVP) to increase water permeability in the principal cells of the collecting duct. AVP is bound to the V2 receptor (a G-protein-linked receptor) on the basolateral membrane. The basic process of G-protein-coupled receptor signaling consists of three steps: a hepta-helical receptor that detects a ligand (in this case, AVP) in the extracellular milieu, a G-protein (Gαs) that dissociates into a subunits bound to guanosine triphosphate and bg subunits after interaction with the ligand-bound receptor and an effector (in this case, adenylyl cyclase) that interacts with dissociated G-protein subunits to generate small molecule second messengers. AVP activates adenylyl cyclase, increasing the intracellular concentration of cAMP. The topology of adenylyl cyclase is characterized by two tandem repeats of six hydrophobic transmembrane domains separated by a large cytoplasmic loop and terminates in a large intracellular tail. The dimeric structure (C1 and C2) of the catalytic domains is represented. Conversion of adenosine triphosphate (ATP) to cAMP takes place at the dimer interface. Two aspartate residues (in C1) coordinate two metal co-factors (Mg2+ or Mn2+ represented here as two small black circles), which enable the catalytic function of the enzyme. Adenosine is shown as an open circle and the three phosphate groups (ATP) are shown as smaller open circles. PKA is the target of the generated cAMP. The binding of cAMP to the regulatory subunits of PKA induces a conformational change, causing these subunits to dissociate from the catalytic subunits. These activated subunits (C) as shown here are anchored to an aquaporin-2 (AQP2)-containing endocytic vesicle via an A-kinase-anchoring protein. The local concentration and distribution of the cAMP gradient are limited by phosphodiesterases (PDEs). Cytoplasmic vesicles carrying the water channels (represented as homotetrameric complexes) are fused to the luminal membrane in response to AVP, thereby increasing the water permeability of this membrane. The dissociation of the A-kinase-anchoring protein from the endocytic vesicle is not represented. Microtubules and actin filaments are necessary for vesicle movement toward the membrane. When AVP is not available, AQP2 water channels are retrieved by an endocytic process, and water permeability returns to its original low rate. Aquaporin-3 (AQP3) and aquaporin-4 (AQP4) water channels are expressed constitutively at the basolateral membrane.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4400507&req=5

fig5: Schematic representation of the effect of vasopressin (AVP) to increase water permeability in the principal cells of the collecting duct. AVP is bound to the V2 receptor (a G-protein-linked receptor) on the basolateral membrane. The basic process of G-protein-coupled receptor signaling consists of three steps: a hepta-helical receptor that detects a ligand (in this case, AVP) in the extracellular milieu, a G-protein (Gαs) that dissociates into a subunits bound to guanosine triphosphate and bg subunits after interaction with the ligand-bound receptor and an effector (in this case, adenylyl cyclase) that interacts with dissociated G-protein subunits to generate small molecule second messengers. AVP activates adenylyl cyclase, increasing the intracellular concentration of cAMP. The topology of adenylyl cyclase is characterized by two tandem repeats of six hydrophobic transmembrane domains separated by a large cytoplasmic loop and terminates in a large intracellular tail. The dimeric structure (C1 and C2) of the catalytic domains is represented. Conversion of adenosine triphosphate (ATP) to cAMP takes place at the dimer interface. Two aspartate residues (in C1) coordinate two metal co-factors (Mg2+ or Mn2+ represented here as two small black circles), which enable the catalytic function of the enzyme. Adenosine is shown as an open circle and the three phosphate groups (ATP) are shown as smaller open circles. PKA is the target of the generated cAMP. The binding of cAMP to the regulatory subunits of PKA induces a conformational change, causing these subunits to dissociate from the catalytic subunits. These activated subunits (C) as shown here are anchored to an aquaporin-2 (AQP2)-containing endocytic vesicle via an A-kinase-anchoring protein. The local concentration and distribution of the cAMP gradient are limited by phosphodiesterases (PDEs). Cytoplasmic vesicles carrying the water channels (represented as homotetrameric complexes) are fused to the luminal membrane in response to AVP, thereby increasing the water permeability of this membrane. The dissociation of the A-kinase-anchoring protein from the endocytic vesicle is not represented. Microtubules and actin filaments are necessary for vesicle movement toward the membrane. When AVP is not available, AQP2 water channels are retrieved by an endocytic process, and water permeability returns to its original low rate. Aquaporin-3 (AQP3) and aquaporin-4 (AQP4) water channels are expressed constitutively at the basolateral membrane.
Mentions: The transfer of water across the principal cells of the collecting ducts is now known at such a detailed level that billions of molecules of water traversing the membrane can be represented; see useful teaching tools at http://www.mpibpc.gwdg.de/abteilungen/073/gallery.html and http://www.ks.uiuc.edu/research/aquaporins. The 2003 Nobel Prize in chemistry was awarded to Peter Agre and Roderick MacKinnon, who solved two complementary problems presented by the cell membrane: how does a cell let one type of ion through the lipid membrane to the exclusion of other ions? And how does it permeate water without ions? This contributed to creating momentum and renewed interest in basic discoveries related to the transport of water and indirectly to diabetes insipidus [57, 58]. The first step in the action of AVP (Synthetized by du Vigneaud, Nobel Prize in Chemistry 1955) [59] on water excretion is its binding to arginine vasopressin type 2 receptors (hereafter referred to as V2 receptors) on the basolateral membrane of the collecting duct cells (Figure 5). The human AVPR2 gene that codes for the V2 receptor is located in the chromosome region Xq28 and has three exons and two small introns [12, 60]. The sequence of the complementary DNA predicts a polypeptide of 371 amino acids with seven transmembrane, four extracellular and four cytoplasmic domains. The activation of the V2 receptor on renal collecting tubules stimulates adenylyl cyclase via the stimulatory G protein (Gs) (1994 Nobel Prize in Physiology and Medicine to Rodbell and Gilman for signal transduction and G-proteins) and promotes the cAMP-mediated incorporation of water channels into the luminal surface of these cells [61]. E. Sutherland and T. Rall isolated cAMP in 1956 and Sutherland was awarded the Nobel Prize in Physiology or Medicine in 1971 [62]. There are two ubiquitously expressed intracellular cAMP receptors: (i) the classical protein kinase A (PKA) that is a cAMP-dependent protein kinase and (ii) the recently discovered exchange protein directly activated by cAMP that is a cAMP-regulated guanine nucleotide exchange factor. Both these receptors contain an evolutionally conserved cAMP-binding domain that acts as a molecular switch for sensing intracellular cAMP levels to control diverse biological functions [63]. Several proteins participating in the control of cAMP-dependent AQP2 trafficking have been identified; for example, A-kinase-anchoring proteins tethering PKA to cellular compartments; phosphodiesterases regulating the local cAMP level; cytoskeletal components such as F-actin and microtubules; small GTPases of the Rho family controlling cytoskeletal dynamics; motor proteins transporting AQP2-bearing vesicles to and from the plasma membrane for exocytic insertion and endocytic retrieval and SNAREs inducing membrane fusions, hsc70, a chaperone important for endocytic retrieval. These processes are the molecular basis of the vasopressin-induced increase in the osmotic water permeability of the apical membrane of the collecting tubule [64–66].

Bottom Line: Patients with polyhydramnios, profound polyuria, hyponatremia, hypochloremia, metabolic alkalosis and sensorineural deafness were found to bear BSND mutations.These clinical phenotypes demonstrate the critical importance of the proteins ROMK, NKCC2 and Barttin to transfer NaCl in the medullary interstitium and thereby to generate, together with urea, a hypertonic milieu.This editorial describes two new developments: (i) the genomic information provided by the sequencing of the AQP2 gene is key to the routine care of these patients, and, as in other genetic diseases, reduces health costs and provides psychological benefits to patients and families and (ii) the expression of AQP2 mutants in Xenopus oocytes and in polarized renal tubular cells recapitulates the clinical phenotypes and reveals a continuum from severe loss of function with urinary osmolalities <150 mOsm/kg H2O to milder defects with urine osmolalities >200 mOsm/kg H2O.

View Article: PubMed Central - PubMed

Affiliation: Groupe d'Étude des Protéines Membranaires (GÉPROM), Département de Physiologie, Université de Montréal, Montréal, Québec, Canada ; Centre de Recherche, Hôpital du Sacré-Cœur de Montréal, Montréal, Québec, Canada.

ABSTRACT
It is clinically useful to distinguish between two types of hereditary nephrogenic diabetes insipidus (NDI): a 'pure' type characterized by loss of water only and a complex type characterized by loss of water and ions. Patients with congenital NDI bearing mutations in the vasopressin 2 receptor gene, AVPR2, or in the aquaporin-2 gene, AQP2, have a pure NDI phenotype with loss of water but normal conservation of sodium, potassium, chloride and calcium. Patients with hereditary hypokalemic salt-losing tubulopathies have a complex phenotype with loss of water and ions. They have polyhydramnios, hypercalciuria and hypo- or isosthenuria and were found to bear KCNJ1 (ROMK) and SLC12A1 (NKCC2) mutations. Patients with polyhydramnios, profound polyuria, hyponatremia, hypochloremia, metabolic alkalosis and sensorineural deafness were found to bear BSND mutations. These clinical phenotypes demonstrate the critical importance of the proteins ROMK, NKCC2 and Barttin to transfer NaCl in the medullary interstitium and thereby to generate, together with urea, a hypertonic milieu. This editorial describes two new developments: (i) the genomic information provided by the sequencing of the AQP2 gene is key to the routine care of these patients, and, as in other genetic diseases, reduces health costs and provides psychological benefits to patients and families and (ii) the expression of AQP2 mutants in Xenopus oocytes and in polarized renal tubular cells recapitulates the clinical phenotypes and reveals a continuum from severe loss of function with urinary osmolalities <150 mOsm/kg H2O to milder defects with urine osmolalities >200 mOsm/kg H2O.

No MeSH data available.


Related in: MedlinePlus