FXYD proteins as regulators of the Na,K-ATPase in the kidney

The FXYD gene family has seven members in mammals and others in fish. Five of these (FXYD1, FXYD2, FXYD4, FXYD7, and PLMS from shark) have been shown to alter the activity of the Na,K-ATPase, as described by other papers in this volume. The gene structure of FXYD family members suggests assembly from protein domain modules and gene duplication. The gamma subunit is unique in the family for having alternative splice variants in the coding region and can be posttranslationally modified with different final consequences for enzyme properties. The nonoverlapping distribution of gamma and CHIF (FXYD4) in kidney helps to explain physiological differences in Na(+) affinity among nephron segments. We also detected phospholemman (FXYD1) in kidney. By immunofluorescence, it was found in extraglomerular mesangial cells (EM cells) of the juxtaglomerular apparatus and in the afferent arteriole. Contrary to many reports that only alpha1 and beta1 are expressed in the kidney, we found that alpha2 and beta2 are present, although not in any nephron segment. Both were detected in arterioles, and beta2 was found in the EM cells. In contrast, alpha1, beta1, and gamma were found in adjacent macula densa. Phospholemman, alpha2, and beta2 are proposed to have distinct roles in regulating the sodium pump in structures involved in tubuloglomerular feedback.