Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Na+/H+ exchanger (NHE) activity is regulated by several types of receptors directly coupled to distinct classes (i.e. Gs, Gi, Gq, and G12) of heterotrimeric (alpha beta gamma) GTP-binding proteins (G proteins), which, upon activation, modulate production of various second messengers (e.g. cAMP, cGMP, diacylglycerol, inositol trisphosphate, and Ca2+). Recently, four isoforms of the rat Na+/H+ exchanger were identified by molecular cloning. To examine their intrinsic responsiveness to G protein and second messenger stimulation, three of these isoforms, NHE-1, -2, and -3, were stably expressed in mutant Chinese hamster ovary cells devoid of endogenous NHE activity (AP-1 cells). Incubation of cells with either AIF4-, a general agonist of G proteins, or cholera toxin, a selective activator of G alpha s that stimulates adenylate cyclase, accelerated the rates of amiloride-inhibitable 22Na+ influx mediated by NHE-1 and -2, whereas they inhibited that by NHE-3. Similarly, short term treatment with phorbol 12-myristate 13-acetate, which mimics diacylglycerol activation of protein kinase C (PKC), or with agents (i.e. forskolin, 8-(4-chlorophenylthio)-cAMP, and isobutylmethylxanthine) that lead to activation of cAMP-dependent protein kinase (PKA) also stimulated transport by NHE-1 and NHE-2 but depressed that by NHE-3. The effects of phorbol 12-myristate 13-acetate were blocked by depleting cells of PKC or by inhibiting PKC using chelerythrine chloride, confirming a role for PKC in modulating NHE isoform activities. Likewise, the PKA antagonist, H-89, attenuated the effects of elevated cAMPi on NHE-1, -2, and -3, further demonstrating the regulation by PKA. Unlike cAMPi, elevation of cGMPi by treatment with dibutyryl-cGMP or 8-bromo-cGMP had no influence on NHE isoform activities, thereby excluding the possibility of a role for cGMP-dependent protein kinase in these cells. These data support the concept that the NHE isoforms are differentially responsive to agonists of the PKA and PKC pathways.
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PMID:Plasma membrane Na+/H+ exchanger isoforms (NHE-1, -2, and -3) are differentially responsive to second messenger agonists of the protein kinase A and C pathways. 749 49

Parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHRP) interact with a common G protein-coupled receptor and stimulate production of diverse second messengers (i.e. cAMP, diacylglycerol, and inositol 1,4,5-trisphosphate) that varies depending on the target cell. In renal proximal tubule OK cells, PTH inhibits the activity of the apical membrane Na+/H+ exchanger, although it is unclear whether the signal is transmitted through protein kinase A (PKA) and/or protein kinase C (PKC). To delineate the signaling circuitry, a series of synthetic PTH and PTHRP fragments were used that stimulate the adenylate cyclase-cAMP-PKA and/or phospholipase C-diacylglycerol-PKC pathways. Human PTH-(1-34) and PTHRP-(1-34) stimulated adenylate cyclase and PKC activity, whereas the PTH analogues, PTH-(3-34), PTH-(28-42), and PTH-(28-48), selectively enhanced only PKC activity. However, each peptide fragment inhibited Na+/H+ exchanger activity by 40-50%, suggesting that PKC and possibly PKA were capable of transducing the PTH/PTHRP signal to the transporter. This was corroborated when forskolin and phorbol 12-myristate 13-acetate (PMA), direct agonists of adenylate cyclase and PKC, respectively, both inhibited the Na+/H+ exchanger. The specific PKA antagonist, H-89, abolished the forskolin-mediated suppression of Na+/H+ exchanger activity, but did not prevent the inhibitory effects of PTH-(1-34) or PMA. In comparison, the potent PKC inhibitor, chelerythrine chloride, prevented the inhibition of Na+/H+ exchanger activity mediated by PTH-(28-48) and PMA but did not avert the negative regulation caused by PTH-(1-34) or forskolin. However, inhibition of both PKA and PKC prevented PTH-(1-34)-mediated suppression of Na+/H+ exchanger activity, indicating that PTH-(1-34) acted through both signaling pathways. In addition, Northern blot analysis revealed the presence of only the NHE-3 isoform of the Na+/H+ exchanger in OK cells. In summary, these results demonstrated that NHE-3 is expressed in OK cells and that activation of the PTH receptor can stimulate both the PKA and PKC pathways, each of which can independently lead to inhibition of NHE-3 activity.
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PMID:Parathyroid hormone and parathyroid hormone-related peptide inhibit the apical Na+/H+ exchanger NHE-3 isoform in renal cells (OK) via a dual signaling cascade involving protein kinase A and C. 765 18