Toward a comprehensive molecular model of active calcium reabsorption

Abstract

The fine tuning of Ca2+ excretion in the kidney takes place in the distal nephron, which consists of the distal convoluted tubule, connecting tubule, and initial portion of the cortical collecting duct. In these segments, Ca2+ is reabsorbed through an active transcellular pathway. The apical influx of Ca2+ into the distal renal cell is presumably the rate-limiting step in this process, and its molecular identity has remained obscure so far. The recently discovered epithelial Ca2+ channel (ECaC) exhibits the expected properties for being the gatekeeper in transcellular Ca2+ reabsorption. The characteristics and potential physiological role of ECaC will be discussed in this review. Our knowledge of the mechanisms involved in the regulation of transcellular Ca2+ transport has advanced rapidly since the development of cell models originating from distal tubular cells. Studies using these models indicate that hormones including arginine vasopressin, PGE2, adenosine, ATP, and atrial natriuretic peptide should be considered as calciotropic hormones controlling renal Ca2+ handling. Evidence is now beginning to emerge that the stimulating calciotropic hormones utilize new cAMP-independent pathways to stimulate Ca2+ reabsorption. These new findings allow the development of a comprehensive and detailed model of the process of transcellular calcium transport in the kidney whereby the individual contribution of the participating transporters can now be fully appreciated.