A calcineurin homologous protein is required for sodium-proton exchange events in the C. elegans intestine

Abstract

Caenorhabditis elegans defecation is a rhythmic behavior, composed of three sequential muscle contractions, with a 50-s periodicity. The motor program is driven by oscillatory calcium signaling in the intestine. Proton fluxes, which require sodium-proton exchangers at the apical and basolateral intestinal membranes, parallel the intestinal calcium flux. These proton shifts are critical for defecation-associated muscle contraction, nutrient uptake, and longevity. How sodium-proton exchangers are activated in time with intestinal calcium oscillation is not known. The posterior body defecation contraction mutant (pbo-1) encodes a calcium-binding protein with homology to calcineurin homologous proteins, which are putative cofactors for mammalian sodium-proton exchangers. Loss of pbo-1 function results in a weakened defecation muscle contraction and a caloric restriction phenotype. Both of these phenotypes also arise from dysfunctions in pH regulation due to mutations in intestinal sodium-proton exchangers. Dynamic, in vivo imaging of intestinal proton flux in pbo-1 mutants using genetically encoded pH biosensors demonstrates that proton movements associated with these sodium-proton exchangers are significantly reduced. The basolateral acidification that signals the first defecation motor contraction is scant in the mutant compared with a normal animal. Luminal and cytoplasmic pH shifts are much reduced in the absence of PBO-1 compared with control animals. We conclude that pbo-1 is required for normal sodium-proton exchanger activity and may couple calcium and proton signaling events.

Calcineurin homologous protein: a multifunctional Ca2+-binding protein family

“…Indeed, it was recently found that loss of Caenorhabditis elegans (C. elegans) chp1 orthologous, pbo-1 (posterior body contraction mutant) function results in a weakened defecation muscle contraction and a caloric-restriction phenotype of C. elegans. Pbo-1 affects defecation in C. elegans by regulating differentially the activity of intestinal NHE exchangers located at the apical and basolateral intestinal membranes of C. elegans (149). Further studies using this and other animal models may aid identifying the global effects of losing CHP function.…”

Membrane ion transport in non-excitable tissues

“…Consistent with this idea, a reduction in either nhx-2 or vha-6 expression or activity is associated with reduced fat stores and increased lifespan (Nehrke, 2003; Allman et al, 2009; Wagner et al, 2011). This is consistent with the idea that nutrient deprivation extends lifespan but that too much deprivation—such as might occur in the loss-of-function nhx-2 and vha-6 mutants—leads to starvation.…”

The C. elegans CHP1 homolog, pbo-1, functions in innate immunity by regulating the pH of the intestinal lumen

“…It is reasonable to propose that ingestion of pathogens triggers a shift from defecation (muscle contraction) to pathogen defense (production of H 2 O 2 ) in C. elegans. The PBO-1 and PBO-4 proteins are conserved in mammalian cells [15,16] and it will be interesting to determine whether these proteins have a similar role in regulating pH and immune function in higher species.…”

“…PBO-1 was first identified because of its contribution to the posterior body contraction (Pbo) phenotype [14]. PBO-1 is an EF-hand protein orthologous to human CHP1 (Calcineurin B homologous protein 1, also called P22) [15]. It is thought that PBO-1 links the release of intracellular calcium to the activity and/or trafficking of Na + /H + -exchangers (NHE or NHX), including NHX-2, NHX-6 and PBO-4 (also known as NHX-7) [16].…”