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PAM mediates sustained inhibition of cAMP signaling by sphingosine‐1‐phosphate
Author(s) -
Pierre Sandra C,
Häusler Julia,
Birod Kerstin,
Geisslinger Gerd,
Scholich Klaus
Publication year - 2004
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7600321
Subject(s) - philosophy , art history , humanities , art
PAM (Protein Associated with Myc) is an almost ubiquitously expressed protein that is one of the most potent inhibitors of adenylyl cyclase activity known so far. Here we show that PAM is localized at the endoplasmic reticulum in HeLa cells and that upon serum treatment PAM is recruited to the plasma membrane, causing an inhibition of adenylyl cyclase activity. We purified the serum factor that induced PAM translocation and identified it as sphingosine‐1‐phosphate (S1P). Within 15 min after incubation with S1P, PAM appeared at the plasma membrane and was detectable for up to 120 min. Sphingosine‐1‐phosphate induced adenylyl cyclase inhibition in two phases: an initial (1–10 min) and a late (20–240 min) phase. The initial adenylyl cyclase inhibition was G i ‐mediated and PAM independent. In the late phase, adenylyl cyclase inhibition was PAM dependent and attenuated cyclic AMP (cAMP) signaling by various cAMP‐elevating signals. This makes PAM the longest lasting nontranscriptional regulator of adenylyl cyclase activity known to date and presents a novel mechanism for the temporal regulation of cAMP signaling.