The type III inositol 1,4,5-trisphosphate receptor is phosphorylated by cAMP-dependent protein kinase at three sites

IP3 (inositol 1,4,5 -tri sphosph ate) receptors form tetrameric, lP(3)- gated Ca2+ channels in endoplasmic reticulum membranes, and are substrates for several kinases, including PKA (cAMP-dependent protein kinase). Activation of PKA has been reported to either enhance or inhibit type IIIIP3 receptor Ca2+-channel activity, but, as yet, the sites of phosphorylation remain unknown. Here, we reveal that PKA phosphorlates the type III IP3 receptor at Ser(916), Ser(934) and Ser(1832), and that, intriguingly, each site is located close to a putative surface-exposed peptide loop. Furthermore, we demonstrate that Ser(934) is considerably more susceptible to PKA-dependent phoshorylation than either Ser(916) or Ser(1832). These findings define the sites at which the type III IP3 receptor is phosphorylated by PKA, and provide the basis for exploring the functional consequences of this regulatory event.