Parathyroid hormone signaling in bone and kidney

Abstract

PTH activates a number of different signaling pathways by binding to a single receptor in bone and kidney. Recent studies demonstrate the involvement of novel factors as well as additional roles for previously identified downstream factors of PTH.

Parathyroid hormone (PTH) rapidly enhances CFTR-mediated HCO3− secretion in intestinal epithelium-like Caco-2 monolayer: a novel ion regulatory action of PTH

“…PTHR1 was previously reported to be the sole functional receptor for renal distal tubular Ca 2ϩ reuptake and bone resorption (35), whereas the ion regulatory function of PTHR2 remained elusive. The downstream signaling pathways of PTH were herein demonstrated to be cAMP/PKA-and PI3K-dependent.…”

“…Generally, in mammals including humans and rodents, PTH enhances the intestinal Ca 2ϩ absorption indirectly by stimulating renal synthesis of 1,25(OH) 2 D 3 (54). Since PTH increased the intracellular cAMP levels in most target cells (35), and the cAMP-regulated ion transporters (e.g., CFTR, NHE1, NHE3, NBCe1, and Na ϩ -K ϩ -ATPase) were abundant in mammalian intestinal cells (30,51,64), it was possible that PTH could directly activate these transporters, leading to ion transport across mammalian intestinal epithelium.…”

“…Impedance spectroscopy was performed by using 1255B frequency response analyzer and 1287A electrochemical interface (Solartron, Farnborough, UK). Sine-wave alternating current (35 A/cm 2 root mean square amplitude, 0.5 Hz-10 kHz) was applied across Caco-2 monolayer at different time points, i.e., before adding 10 nmol/l PTH 1-34 or 10 mol/l forskolin, and at 1,5,10,15,20,25,30,35 (Fig. 1A) was automatically analyzed by Zplot/Zview.…”

“…Several cAMP-producing mediators, such as vasoactive intestinal peptide (VIP) and forskolin, not only induced CFTR opening but also stimulated recruitment of vesicular CFTR to the apical membrane (2). Since PTH has been reported to elevate intracellular cAMP levels (35), it was possible that PTH induced cAMP-dependent CFTR activation, thereby stimulating anion secretion in intestinal epithelial cells. By using alternating current (AC) impedance spectroscopy, one could demonstrate whether PTH induced CFTR opening and/or fusion of CFTR-rich vesicles to the apical membrane, because these processes usually affect the resistive and capacitive properties of the plasma membrane, respectively (12,40,44,50).…”

“…The peak I sc changes (i.e., ⌬I sc ) were calculated at the V t peak responses and were later used to represent electrogenic ion transport across the monolayer. Since PTH 1-34 is known to exert its actions through a cAMP-dependent PKA signaling pathway (35), an adenylyl cyclase activator, forskolin, was applied to the basolateral side. Similar to PTH, forskolin rapidly induced the V t peak response within 80.00 Ϯ 6.71 s (n ϭ 6), followed by a sustained negative-potential plateau (Fig.…”