Involvement of calmodulin in mediating inhibitory action of intracellular Ca2+ on renin secretion

Park, C. S.; Honeyman, Thomas W.; Chung, Eunhee; Lee, J. S.; Sigmon, David H.; Fray, J. C. S.

doi:10.1152/ajprenal.1986.251.6.f1055

Cited by 20 publications

(33 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These isoforms have been characterized as inhibited by G i , stimulated by forskolin, GTP analogues, and other hormones or factors, which are typically adenylyl cyclase agonists. 21,23,24 They respond to submicromolar changes in intracellular calcium, 24 consistent with the small changes calculated by Park et al, 25 which can alter renin secretion.…”

Section: Discussionsupporting

confidence: 85%

“…Again, this observation supports our hypothesis that the decrease in calcium activates adenylyl cyclase, resulting in cAMP formation and, subsequently, renin release. It suggests that basal levels of intracellular calcium quench adenylyl cyclase activity, as predicted by Park et al, 25 and that reducing the intracellular calcium further stimulates (or disinhibits) its enzymatic activity. The actual mechanism by which cAMP stimulates the release of renin is not understood beyond its effect on cAMP-dependent protein kinase A or interacting with some other cAMP-binding protein promoting an undefined cascade that results in renin release from storage granules in the JG cells.…”

Section: Discussionmentioning

confidence: 71%

See 1 more Smart Citation

Decreased Intracellular Calcium Stimulates Renin Release via Calcium-Inhibitable Adenylyl Cyclase

et al. 2007

View full text Add to dashboard Cite

Abstract-Intracellular calcium and cAMP are the 2 second messengers that regulate renin release; cAMP stimulates renin release from juxtaglomerular (JG) cells, whereas increased intracellular calcium inhibits it. We hypothesized that decreased intracellular calcium acts by activating calcium-inhibitable isoforms of adenylyl cyclase, increasing cAMP, and stimulating renin secretion. We used a primary culture of JG cells isolated from C-57/B6 mice. Cells were plated to a density of 70% in serum-free medium and incubated for 2 hours with or without 100 mol/L of the cytosolic calcium chelator 5Ј5-dimethyl-1,2-bis-(2-aminophenoxy)-ethane-N,N,NЈ,NЈ-tetra-acetic acid (BAPTA-AM) to decrease intracellular calcium. JG cell cAMP content and renin release were determined by radioimmunoassay. Key Words: renin Ⅲ adenylyl cyclase Ⅲ calcium Ⅲ juxtaglomerular cell Ⅲ cAMP R enin is the rate-limiting enzymatic step in the formation of angiotensin (Ang); thus, control of renin secretion by the kidney is a critical element in regulating systemic blood pressure and renal function. The common element in all of the renin-stimulating pathways is the second messenger cAMP, 1 the product of adenylyl cyclase activity. 2 However, it is also well established that renin secretion by the JG cells, unlike almost all secretory cells, is inversely related to intracellular calcium concentration such that paradoxically elevated intracellular calcium is a potent inhibitor of renin release. [3][4][5] Increased calcium in the juxtaglomerular (JG) cells suppresses basal renin release and blunts stimulation of renin secretion. 6 -9 Decreased JG cell intracellular calcium increases basal renin secretion and amplifies stimulated renin levels. 3,6,9 -11 Although the influence of these 2 "second messenger" regulatory signals, cAMP and calcium, has been established for years, 1,5,6,10,12 the precise nature of their interactions is unresolved and an area of considerable interest and debate.There are at least 9 isoforms of adenylyl cyclase, 2 including 2 (types V and VI) that are inhibited by increased intracellular calcium. 13 Because renin release is inhibited by increased intracellular calcium and stimulated by cAMP, we hypothesized that reducing intracellular calcium stimulates renin release by activating a calcium-inhibitable adenylyl cyclase, types V and/or VI in JG cells, enhancing cAMP levels, and thereby stimulating renin release. To test this hypothesis, we used primary cultures of isolated mouse JG cells, which exhibit the classic phenotypic character of the JG cell but are unencumbered by the many extracellular signaling pathways that can influence renin secretion in vivo or in less homogeneous in vitro preparations. Our results provide a unique answer to this longstanding question of how these 2 classic second messengers interact to control the release of renin from the JG cell.

show abstract

Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 71%

Decreased Intracellular Calcium Stimulates Renin Release via Calcium-Inhibitable Adenylyl Cyclase

et al. 2007

View full text Add to dashboard Cite

show abstract

“…W-7 had its effect when the CaSR was activated by cinacalcet or when we used 1.2 mM Ca media, but not with the 0.9 mM Ca media. As we and others have previously shown (11,19,32), W-7 increased basal renin release, as well as cAMP. Thus, our data supports the hypothesis that the influence of calmodulin on renin is coupled to PDE1C in the JG cells, as in other cell types (3,5), and provides a novel explanation for the previously unexplained role of calmodulin in regulating renin.…”

Section: Discussionsupporting

confidence: 77%

“…When we combined these two inhibitors, there was no additive effect. It has been shown repeatedly since 1983 that calmodulin is involved in some way with the Ca paradox and Ca-mediated inhibition of renin secretion (11,19,32). A variety of calmodulin inhibitors, including calmidazolium, W-7, W-13, and trifluoperazine, all similarly increased renin release (32) from dog and rabbit renal cortical slices.…”

Section: Discussionmentioning

confidence: 99%

Calcium-dependent phosphodiesterase 1C inhibits renin release from isolated juxtaglomerular cells

Ortiz-Capisano

Liao

Ortíz

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

View full text Add to dashboard Cite

release from the juxtaglomerular (JG) cell is stimulated by the second messenger cAMP and inhibited by calcium. We previously showed JG cells contain a calcium sensing receptor (CaSR), which, when stimulated, decreases cAMP formation and inhibits renin release. We hypothesize CaSR activation decreases cAMP and renin release, in part, by stimulating a calcium calmodulin-activated phosphodiesterase 1 (PDE1). We incubated our primary culture of JG cells with two selective PDE1 inhibitors [8-methoxymethil-IBMX (8-MM-IBMX; 20 M) and vinpocetine (40 M)] and the calmodulin inhibitor W-7 (10 M) and measured cAMP and renin release. Stimulation of the JG cell CaSR with the calcimimetic cinacalcet (1 M) resulted in decreased cAMP from a basal of 1.13 Ϯ 0.14 to 0.69 Ϯ 0.08 pM/mg protein (P Ͻ 0.001) and in renin release from 0.89 Ϯ 0.16 to 0.38 Ϯ 0.08 g ANG I/ml ⅐ h Ϫ1 ⅐ mg protein Ϫ1 (P Ͻ 0.001). However, the addition of 8-MM-IBMX with cinacalcet returned both cAMP (1.10 Ϯ 0.19 pM/mg protein) and renin (0.57 Ϯ 0.16 g ANG I/ml ⅐ h Ϫ1 ⅐ mg protein Ϫ1 ) to basal levels. Similar results were obtained with vinpocetine, and also with W-7. Combining 8-MM-IBMX and W-7 had no additive effect. To determine which PDE1 isoform is involved, we performed Western blot analysis for PDE1A, B, and C. Only Western blot analysis for PDE1C showed a characteristic band apparent at 80 kDa. Immunofluorescence showed cytoplasmic distribution of PDE1C and renin in the JG cells. In conclusion, PDE1C is expressed in isolated JG cells, and contributes to calcium's inhibitory modulation of renin release from JG cells.angiotensin; calmodulin; phosphodiesterase; cAMP; adenylyl cyclase RENIN IS THE RATE-LIMITING enzymatic step in the production of angiotensin, a hormone that integrates cardiovascular and renal function in the control of blood pressure as well as salt and volume homeostasis (33). Renin is produced by, stored in, and released from juxtaglomerular (JG) cells, which are derived from renin progenitor cells (42) and are located in the afferent arteriole near the hilus of the glomerulus (2, 43, 35). Two main intracellular second messenger systems are known to regulate renin synthesis and secretion: the cyclic nucleotide, cyclic adenosine monophosphate (cAMP) (8, 41), and intracellular calcium (Ca) (21).Renin secretion by the JG cells demonstrates a paradoxical inverse relationship with intracellular calcium concentration, such that millimolar changes in extracellular Ca or micromolar elevations in intracellular calcium retard renin release (1,9,14,20,22). The primary second messenger involved in the regulation of renin release is cAMP (8), and the concentration of cAMP in cells is determined by a balance between the rate of cAMP generation by adenylyl cyclases and cAMP hydrolysis by phosphodiesterases (PDE) (7, 16). We (30, 31), and also Grünberger et al. (18), have reported JG cells express calciuminhibitable adenylyl cyclase (27). Furthermore, we have identified the JG-specific isoform-regulating renin release to be adenylyl cyclase type V (30)...

show abstract

“…intracellular calcium concentration and the release of renin and that intracellular calcium at normal or elevated levels inhibits renin release through a calmodulinmediated process. However, the subsequent components of the inhibitory cascade induced by increasing intracellular calcium are not yet defined.Because increasing intracellular calcium both stimulates NO synthesis and inhibits renin release using in vitro preparations from the renal cortex and NO also inhibits renin, it seemed a logical hypothesis that at least part of the inhibitory effect of calcium on renin release is due to calcium-dependent NO synthesis and the subsequent inhibitory influence of NO (presumably through cGMP-mediated inhibition of renin).To test this hypothesis, in vitro experiments were carried out with the use of rat renal cortical slices based on the techniques and observations previously used to show inhibition of renin by both calcium and calmodulin 13 and by NO synthesis. 5 The combined results support the possibility that at least part of the inhibition of renin by stimuli that increase intracellular calcium may be attributed to inhibition via the concurrent stimulus of NO synthesis.…”

mentioning

confidence: 99%

Nitric oxide participates in calcium-mediated regulation of renin release.

Beierwaltes

1994

Hypertension

View full text Add to dashboard Cite

The regulation of renin release is unusual in that intracellular calcium reportedly acts as an inhibitory second messenger. Increased calcium not only inhibits renin release but is a cofactor in nitric oxide synthesis. Also, nitric oxide can inhibit renin release. This study was done in vitro using rat renal cortical slices to determine whether calcium-mediated renin inhibition could be in part due to the concurrent production of nitric oxide. Renin concentration in the incubation medium was determined by radioimmunoassay for angiotensin I (Ang I) generation (in nanograms Ang I per hour per milligram per 30 minutes of incubation). In all studies, n=6 to 17. In normal-calcium incubation medium (2.6 mmol/L), 10~* mol/L /V°-monomethyl L-arginine, which blocks nitric oxide synthesis, caused an 18% increase in basal renin release (78.6±8.9 versus 66.7±5. intracellular calcium concentration and the release of renin and that intracellular calcium at normal or elevated levels inhibits renin release through a calmodulinmediated process. However, the subsequent components of the inhibitory cascade induced by increasing intracellular calcium are not yet defined.Because increasing intracellular calcium both stimulates NO synthesis and inhibits renin release using in vitro preparations from the renal cortex and NO also inhibits renin, it seemed a logical hypothesis that at least part of the inhibitory effect of calcium on renin release is due to calcium-dependent NO synthesis and the subsequent inhibitory influence of NO (presumably through cGMP-mediated inhibition of renin).To test this hypothesis, in vitro experiments were carried out with the use of rat renal cortical slices based on the techniques and observations previously used to show inhibition of renin by both calcium and calmodulin 13 and by NO synthesis. 5 The combined results support the possibility that at least part of the inhibition of renin by stimuli that increase intracellular calcium may be attributed to inhibition via the concurrent stimulus of NO synthesis. MethodsAll the studies were performed with an in vitro preparation incubating renal cortical slices as previously described.

show abstract

Involvement of calmodulin in mediating inhibitory action of intracellular Ca2+ on renin secretion

Cited by 20 publications

References 0 publications

Decreased Intracellular Calcium Stimulates Renin Release via Calcium-Inhibitable Adenylyl Cyclase

Decreased Intracellular Calcium Stimulates Renin Release via Calcium-Inhibitable Adenylyl Cyclase

Calcium-dependent phosphodiesterase 1C inhibits renin release from isolated juxtaglomerular cells

Nitric oxide participates in calcium-mediated regulation of renin release.

Contact Info

Product

Resources

About