Key result
Activation of PKA by cAMP inhibited NHE3 activity in wild-type mouse renal brush border membranes (by 40+/-9%, P<0.01) but had no significant effect in NHERF-1 (-/-) membranes.
Absolute Event Rate: 0.97% vs 0.55%
p-value: p=<0.01
NHERF-1 plays a unique and essential role in the cAMP-mediated inhibition of NHE3 activity in the mouse renal proximal tubule.
NHERF-1 is essential for cAMP-PKA inhibition of NHE3 in mouse proximal tubule; leaves open its role in human renal sodium handling.
Sodium-hydrogen exchanger regulatory factor isoform-1 (NHERF-1) and NHERF-2 are two structurally related PDZ-domain-containing protein adapters that effectively transduce cyclic AMP (cAMP) signals that inhibit NHE3, the sodium-hydrogen exchanger isoform present at the apical surface of kidney and gut epithelia. The mouse renal proximal tubule expresses both NHERF isoforms, suggesting their redundant functions as regulators of renal electrolyte metabolism. To define the role of NHERF-1 in the physiological control of NHE3, we analyzed NHE3 activity in isolated brush border membrane (BBM) preparations from renal proximal tubules of wild-type (WT) and NHERF-1 (-/-) mice. Basal Na(+)-H(+) exchange was indistinguishable in BBMs from WT and NHERF-1 (-/-) mice (0.96+/-0.08 and 0.95+/-0.10 nmol/mg protein/10 s, respectively). Activation of membrane bound cAMP-dependent protein kinase (PKA) by cAMP inhibited NHE3 activity in WT BBMs (0.55+/-0.07 nmol/mg protein/10 s or 40+/-9%, P<0.01) but had no discernible effect on Na(+)-H(+) exchange in the NHERF-1 (-/-) BBM (0.97+/-0.07 nmol/mg protein/10 s; P=not significant). This was associated with a significant decrease in cAMP-stimulated phosphorylation of NHE3 immunoprecipitated from solubilized NHERF-1 (-/-) BBMs. As the protein levels for NHE3, NHERF-2, PKA and ezrin were not changed in the NHERF-1 (-/-) BBMs, the data suggest a unique role for NHERF-1 in cAMP-mediated inhibition of NHE3 activity in the renal proximal tubule of the mouse.
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Weinman et al. (2003) studied this question. NHERF-1 knockout vs. Wild-type (WT) mice was evaluated on NHE3 activity (Na(+)-H(+) exchange) after cAMP activation (p=<0.01). Activation of PKA by cAMP inhibited NHE3 activity in wild-type mouse renal brush border membranes (by 40+/-9%, P<0.01) but had no significant effect in NHERF-1 (-/-) membranes.
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