title: Analysis of Ca2+ signaling motifs that regulate proton signaling through the Na+/H+ exchanger NHX-7 during a rhythmic behavior in Caenorhabditis elegans.
abstract: Membrane proton transporters contribute to pH homeostasis but have also been shown to transmit information between cells in close proximity through regulated proton secretion. For example, the nematode intestinal Na(+)/H(+) exchanger NHX-7 causes adjacent muscle cells to contract by transiently acidifying the extracellular space between the intestine and muscle. NHX-7 operates during a Ca(2+)-dependent rhythmic behavior and contains several conserved motifs for regulation by Ca(2+) input, including motifs for calmodulin and phosphatidylinositol 4,5-bisphosphate binding, protein kinase C- and calmodulin-dependent protein kinase type II phosphorylation, and a binding site for calcineurin homologous protein. Here, we tested the idea that Ca(2+) input differentiates proton signaling from pH housekeeping activity. Each of these motifs was mutated, and their contribution to NHX-7 function was assessed. These functions included pH recovery from acidification in cells in culture expressing recombinant NHX-7, extracellular acidification measured during behavior in live moving worms, and muscle contraction strength as a result of this acidification. Our data suggest that multiple levels of Ca(2+) input regulate NHX-7, whose transport capacity normally exceeds the minimum necessary to cause muscle contraction. Furthermore, extracellular acidification limits NHX-7 proton transport through feedback inhibition, likely to prevent metabolic acidosis from occurring. Our findings are consistent with an integrated network whereby both Ca(2+) and pH contribute to proton signaling. Finally, our results obtained by expressing rat NHE1 in Caenorhabditis elegans suggest that a conserved mechanism of regulation may contribute to cell-cell communication or proton signaling by Na(+)/H(+) exchangers in mammals.
authors: Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA.
authors: Erik
authors: E
authors: Allman
authors: Korrie
authors: K
authors: Waters
authors: Sarah
authors: S
authors: Ackroyd
authors: Keith
authors: K
authors: Nehrke
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D015374:Biosensing Techniques; D017173:Caenorhabditis elegans / Q000235:genetics / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins; D002118:Calcium / Q000737:chemistry / Q000378:metabolism*; D020013:Calcium Signaling; D002147:Calmodulin / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D008954:Models, Biological; D016296:Mutagenesis; D011522:Protons; D015398:Signal Transduction; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000502:physiology*; D013329:Structure-Activity Relationship
chemical_list: D029742:Caenorhabditis elegans Proteins; D002147:Calmodulin; C527532:PBO-4 protein, C elegans; D011522:Protons; D017923:Sodium-Hydrogen Exchangers; D002118:Calcium