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)

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR). The resulting disease is pleiotropic consistent with the idea that CFTR acts as a node within a network of signalling proteins. CFTR is not only a regulator of multiple transport proteins and controlled by numerous kinases but also participates in many signalling pathways that are disrupted after expression of its commonest mutant (F508del-CFTR). It operates in membrane compartments creating a scaffold for cytoskeletal elements, surface receptors, kinases and phosphodiesterases. CFTR is exposed to membrane-local second messengers such that a CFTR-interacting, low cellular energy sensor kinase (AMP- and ADP-activated kinase, AMPK) signals through a high energy phosphohistidine protein kinase (nucleoside diphosphate kinase, NDPK). CFTR also translocates a Ca(2+)-dependent adenylate cyclase to its proximity so that a rigid separation between cAMP-dependent and Ca(2+)-dependent regulation of Cl(-) transport becomes obsolete. In the presence of wild-type CFTR, parallel activation of CFTR and outwardly rectifying anoctamin 6 Cl(-) channels is observed, while the Ca(2+)-activated anoctamin 1 Cl(-) channel is inhibited. In contrast, in CF cells, CFTR is missing/mislocalized and the outwardly rectifying chloride channel is attenuated while Ca(2+)-dependent Cl(-) secretion (anoctamin 1) appears upregulated. Additionally, we consider the idea that F508del-CFTR when trapped in the endoplasmic reticulum augments IP3-mediated Ca(2+) release by providing a shunt pathway for Cl(-). CFTR and the IP3 receptor share the characteristic that they both assemble their partner proteins to increase the plasticity of their hub responses. In CF, the CFTR hub fails to form at the plasma membrane, with widespread detrimental consequences for cell signalling.
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PMID:CFTR: a hub for kinases and crosstalk of cAMP and Ca2+. 2389 8

Anoctamins (ANOs) are multifunctional membrane proteins that consist of 10 homologs. ANO1 (TMEM16A) and ANO2 (TMEM16B) are anion channels activated by intracellular calcium that meditate numerous physiological functions. ANO6 is a scramblase that redistributes phospholipids across the cell membrane. The other homologs are not well characterized. We found ANO9/TMEM16J is a cation channel activated by a cAMP-dependent protein kinase A (PKA). Intracellular cAMP-activated robust currents in whole cells expressing ANO9, which were inhibited by a PKA blocker. A cholera toxin that persistently stimulated adenylate cyclase activated ANO9 as did the application of PKA. The cAMP-induced ANO9 currents were permeable to cations. The cAMP-dependent ANO9 currents were augmented by intracellular Ca2+. Ano9 transcripts were predominant in the intestines. Human intestinal SW480 cells expressed high levels of Ano9 transcripts and showed PKA inhibitor-reversible cAMP-dependent currents. We conclude that ANO9 is a cation channel activated by a cAMP/PKA pathway and could play a role in intestine function.
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PMID:Anoctamin 9/TMEM16J is a cation channel activated by cAMP/PKA signal. 2960 66