Cell Biology

Soluble Adenylyl Cyclase Triggers a Nuclear cAMP Cascade

Science's STKE  24 Feb 2004:
Vol. 2004, Issue 221, pp. tw67-TW67
DOI: 10.1126/stke.2212004TW67

Soluble adenylyl cyclase (sAC) is a recently identified nontransmembrane enzyme that is localized to various subcellular compartments and produces adenosine 3′,5′-monophosphate (cAMP) in response to bicarbonate. Bicarbonate is produced as a by-product of metabolism, and its concentration is altered in response to changes in intracellular pH. Zippin et al. determined that sAC, the regulatory subunits of protein kinase A (PKA), and the phosphorylated form of the PKA target cAMP-response element binding protein (CREB) were colocalized in the nuclei of a subset of hepatocytes in liver sections. Exposure of cultured cell lines (Huh7 cells) to bicarbonate stimulated CREB phosphorylation more rapidly than CREB phosphorylation was stimulated by G protein-coupled receptor activation. Cell fractionation studies of HeLa cells showed that CREB, sAC, and PKA regulatory subunits were present in the nuclear fraction. AC activity in the HeLa nuclear fraction was inhibited by sAC selective inhibitors. Nuclear AC activity was not stimulated by forskolin, which stimulates the transmembrane form of AC; instead, nuclear AC activity was increased in response to bicarbonate. A subset of isolated nuclei showed increased CREB phosphorylation in response to addition of either cAMP or bicarbonate, the latter of which could be blocked by addition of sAC inhibitors. Because cAMP produced by transmembrane ACs is believed to be limited by phosphodiesterase activity, sAC may serve the cell as a mechanism for using cAMP signaling in response to intrinsic cell signals, which are independent of extracellular stimuli that stimulate transmembrane AC.

J. H. Zippin, J. Farrell, D. Huron, M. Kamenetsky, K. C. Hess, D. A. Fischman, L. R. Levin, J. Buck, Bicarbonate-responsive "soluble" adenylyl cyclase defines a nuclear cAMP microdomain. J. Cell. Biol. 164, 527-534 (2004). [Abstract] [Full Text]