Cellular mode of action of parathyroid hormone

The current understanding of the cellular mode of action of PTH has undergone deep changes during the last decade and the major acquisitions can be summarized as follows. First, results from biochemical and cell biology studies suggest the existence of at least two receptor types coupled to two distinct intracellular signaling pathways by G proteins: the phospholipase C-calcium-protein kinase C pathway would be coupled to high-affinity receptors, whereas the adenylate cyclase-cAMP-protein kinase A pathway would be coupled to low-affinity receptors. Until now, only one type of PTH receptor has been identified at the molecular level. It is very likely that additional PTH receptor types will be evidenced. Second, both PTH receptor-coupled transduction pathways are involved in the inhibitory effect of the hormone on the activity of two transport systems of the apical membrane of proximal tubular cells: Na-Pi cotransport and Na-H exchanger. These effects are the cellular basis for PTH inhibition of Pi and bicarbonate reabsorption. Which proteins are the targets of the different protein kinases remains to be established. Concerning the other effects of PTH on the proximal tubule (stimulation of neoglucogenesis and of calcitriol synthesis, and Na, K-ATPase inhibition), protein kinase C seems to play a major role. Third, in Henle's loop, PTH stimulates reabsorption of divalent cations through a dual effect under the dependence of protein kinase A, i.e., enhanced epithelial potential difference and opening of paracellular pathway. Finally, stimulation of distal calcium reabsorption results from multiple events: membrane insertion of apical calcium channels, opening of basolateral chloride channels resulting in cellular hyperpolarization, and modulation of Ca-ATPase. Again, while it is commonly acknowledged that both transduction systems are involved, their precise molecular targets remain to be identified (Table 1). The elucidation of the cellular mode of action of PTH, some examples of which have been reviewed, holds major interest far beyond the field of cell or organ physiology. It is the basis for understanding and, ultimately, for comprehensive treatment of genetic diseases characterized by functional abnormalities of molecules involved in the cascade of events leading to the effect of PTH on its cellular targets (hormone receptors, G proteins, and kinases). The second perspective is pharmacologic: molecular and structural identification of PTH-receptor interactions will be a prelude to design and synthesis of new selective, nonpeptidic hormonal analogs and antagonists that are easier to handle. The high incidence and severity of secondary hyperparathyroidism during chronic renal failure highlights the importance of this research.