Renal adenylate cyclase and the interrelationship between parathyroid hormone and vitamin D in the regulation of urinary phosphate and adenosine cyclic 3',5'-monophosphate excretion.

Forte, Leonard R.; Nickols, G. Allen; Anast, Constantine S.

doi:10.1172/jci108311

Cited by 97 publications

(26 citation statements)

References 31 publications

(16 reference statements)

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“…Taken these together, it is possible that urinary cAMP response to exogenous PTH could diminish to the extent of PHP type I in some patients with severe vitamin D deficiency with markedly elevated endogenous PTH levels, as in our case 1. As suggested by others, chronic elevation in plasma PTH might induce desensitization of PTH receptors and lead to the development of hormone resistance [19,[31][32][33]. tions were higher in strict vegetarians compared with controls [36].…”

Section: Discussionmentioning

confidence: 72%

Vitamin D deficiency in two young adults with biochemical findings resembling pseudohypoparathyroidism type I and type II

et al. 2010

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abstract.We report two patients with vitamin D deficiency due to unbalanced diet. The patients initially presented with severe hypocalcemia, normophosphatemia and markedly elevated serum PTH levels. Although nutritional vitamin D deficiency was suspected from their history of gastrointestinal problems and dietary restriction, we conducted EllsworthHoward test to exclude the possibility of pseudohypoparathyroidism (PHP). Both patients showed no incremental response of urinary phosphate excretion. However, the urinary cAMP response to exogenous PTH was different between the two. Case 1 showed a blunted response (5-fold and 1.54 µmol/h increase) and case 2 showed a normal response (39-fold and 3.04 µmol/h increase). According to the criteria of Ellsworth-Howard test, the data of case 1 was compatible with PHP type I, and of case 2 with PHP type II. The final diagnosis of vitamin D deficiency was established in both patients based on very low serum 25-hydroxyvitamin D levels (less than 5 ng/mL) and the effect of treatment. After calcium supplementation with or without vitamin D, their biochemical abnormalities disappeared. They maintained normocalcemia without medication after correction of their unbalanced diet. The present study indicated that patients with vitamin D deficiency occasionally showed biochemical findings suggestive of PHP and that such patients could exhibit not only PHP type II pattern of response to exogenous PTH but also of type I pattern. Thus our clinical observation suggests the complexity of PTH resistance in vitamin D deficiency and underscores the importance of diet to prevent the disorder.

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Section: Discussionmentioning

confidence: 72%

Vitamin D deficiency in two young adults with biochemical findings resembling pseudohypoparathyroidism type I and type II

et al. 2010

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“…However, in the intact rat, even large doses of PTH given as prolonged infusions or as serial bolus injections failed to elicit refractoriness in vivo, despite the concurrent in vitro evidence of this phenomenon (2). Studies in chicks (29) and rats (30) that were made secondarily hyperparathyroid by dietary deficiency of vitamin D or calcium have shown evidence of tachyphylaxis both in vivo and in vitro; however, the possible influence of concomitant hypocalcemia on these results was not evaluated. The applicability of these findings to human studies is uncertain because there are significant interspecies differences in the effect of PTH on cAMP production and excretion (13,20,31) as well as intraspecies variability in the responses to different PTH preparations (13).…”

Section: Resultsmentioning

confidence: 99%

Rapid development of renal resistance to low doses of synthetic bovine parathyroid hormone fragment 1-34. Dissociation of urinary cyclic adenosine monophosphate, phosphaturic, and calciuric responses.

Law¹,

Heath²

1983

J. Clin. Invest.

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A B S T R A C T The designing of parathyroid hormone (PTH)-renal dose-response studies in human beings is complicated by the possibility of rapid homologous receptor down-regulation, a phenomenon that is clearly shown to occur in vitro. Large amounts of PTH given to human subjects as serial injections or prolonged infusions cause decreased urinary 3',5'-cyclic adenosine monophosphate (cAMP) responses to subsequent PTH doses, but it is uncertain whether lower doses given over shorter periods similarly cause renal tachyphylaxis to PTH action. Thus, in seven water-loaded adults, we infused in ascending order 10, 30, 75, 150, and 300 U of synthetic bovine PTH fragment (bPTH 1-34) per 70 kg body wt over 15 min on widely separated days ("separate day administration"). On another day, each subject received all five 15-min doses in ascending order at 75-min intervals ("single day administration"). Urine collection intervals were control, 0-30 min (including the PTH infusion), and 30-60 min. Peak nephrogenous cAMP (NcAMP, nmol/100 ml glomerular filtrate) response was linearly related to the dose of PTH (separate day study, r = 0.94, P < 0.001; single day study, r = 0.88, P < 0.001). However, the slope of NcAMP responses plotted against PTH dose for the single day study was only 36% of that derived from separate day administration of the same PTH doses (P < 0.001). After only 40 U (10 + 30) of bPTH 1-34/70 kg, the NcAMP response to 75 U was reduced 44%, and the effect of 300 U/70 kg, when given as the last of the sequential single day infusions, was 64% less than the response to 300 U of bPTH 1-34 given alone (P < 0.001). The phosphaturic response (fractional excretion of phosphorus, FEP [percent]) was also linearly related to bPTH 1-34 dose, but combined administration of the PTH infusions on one day increased FEP at each dose identically with the effects of separate day administration. A transient, dose-related, early hypercalciuric response to bPTH 1-34 also occurred, and was of equal magnitude in both protocols. These studies demonstrate that significant blunting of the NcAMP response to bPTH 1-34 occurs rapidly and follows brief exposure to relatively low doses of hormone. In contrast, there is no effect of recent PTH administration on the phosphaturic and early hypercalciuric actions of bPTH 1-34. This seeming dissociation of PTH effects makes unclear the physiologic importance of PTH-induced cAMP tachyphylaxis in the regulation of final PTH actions. In any case, studies of NcAMP responses in which the occurrence of tachyphylaxis would be undesirable should be designed to avoid prolonged or closely spaced administrations of the hormone. INTRODUCTION The acute administration of exogenous parathyroid hormone (PTH)' causes increased urinary excretion of

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“…A stimulatory effect of PTH on urinary cAMP excretion has been reported in humans (42), mice (47), rats (27), birds (58), and dogs (78), whereas hamsters were found to be resistant to the effect of PTH (44). In wild-type mice, PTH increased urinary cAMP excretion (64); however, this effect was completely absent in AC6 knockout mice, suggesting that this isoform is required for PTH-stimulated cAMP formation in the kidney.…”

Section: Physiological Effects Of Ac Isoformsmentioning

confidence: 97%

Regulation of nephron water and electrolyte transport by adenylyl cyclases

Rieg

Kohan

2014

American Journal of Physiology-Renal Physiology

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Adenylyl cyclases (AC) catalyze formation of cAMP, a critical component of G protein-coupled receptor signaling. So far, nine distinct membrane-bound AC isoforms (AC1-9) and one soluble AC (sAC) have been identified and, except for AC8, all of them are expressed in the kidney. While the role of ACs in renal cAMP formation is well established, we are just beginning to understand the function of individual AC isoforms, particularly with regard to hormonal regulation of transporter and channel phosphorylation, membrane abundance, and trafficking. This review focuses on the role of different AC isoforms in regulating renal water and electrolyte transport in health as well as potential pathological implications of disordered AC isoform function. In particular, we focus on modulation of transporter and channel abundance, activity, and phosphorylation, with an emphasis on studies employing genetically modified animals. As will be described, it is now evident that specific AC isoforms can exert unique effects in the kidney that may have important implications in our understanding of normal physiology as well as disease pathogenesis.homeostasis; parathyroid hormone; renal disease; signaling; vasopressin NINE DIFFERENT MEMBRANE-BOUND adenylyl cyclase (AC) isoforms in mammals have been described; all of them are key enzymes in catalyzing the conversion of ATP to cAMP. The membrane-bound ACs (which is what this review refers to, unless stated otherwise) have two membrane clusters that each contain six transmembrane domains and three large cytoplasmic domains (N, C1a/b and C2a/b). C1a and C2a form the catalytic core complex; they are highly conserved and homologous to one another. The N-terminal domain varies between AC isoforms and plays a regulatory role (46).A given cell type can express several AC isoforms, binds numerous agonists that modify cAMP production, and has a wide range of cAMP-dependent effects. This begs the question as to how cAMP is able to mediate such a variety of effects yet do this in a specific and highly regulated manner. This review focuses on one aspect of such specificity, namely, the role of unique AC isoforms in mediating particular biological actions in the kidney. However, it is important to briefly discuss the other key factors that play a role in allowing cAMP to exert so many functions, yet in a highly directed manner.The classic paradigm was that G proteins interacted randomly with ACs; i.e., each AC molecule's activity reflected the relative influence of potentially several G protein-coupled receptors (GPCR). However, studies using fluorescent energy transfer-based intracellular probes indicate that AC-derived cAMP (and its downstream effectors) is confined to specific regions within the cell (3,22). Furthermore, recent studies suggest that cAMP synthesis by specific AC isoforms can occur in vesicular compartments due to sustained activity of specific internalized receptors (3). Such association between GPCRs and ACs is likely due, at least in part, to A-kinaseanchoring proteins (AKAPs) th...

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Renal adenylate cyclase and the interrelationship between parathyroid hormone and vitamin D in the regulation of urinary phosphate and adenosine cyclic 3',5'-monophosphate excretion.

Cited by 97 publications

References 31 publications

Vitamin D deficiency in two young adults with biochemical findings resembling pseudohypoparathyroidism type I and type II

Vitamin D deficiency in two young adults with biochemical findings resembling pseudohypoparathyroidism type I and type II

Rapid development of renal resistance to low doses of synthetic bovine parathyroid hormone fragment 1-34. Dissociation of urinary cyclic adenosine monophosphate, phosphaturic, and calciuric responses.

Regulation of nephron water and electrolyte transport by adenylyl cyclases

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