The type III inositol 1,4,5-trisphosphate receptor is phosphorylated by cAMP-dependent protein kinase at three sites.
IP3 (inositol 1,4,5-trisphosphate) receptors form tetrameric, IP3-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 III IP3 receptor Ca2+-channel activity, but, as yet, the sites of phosphorylation remain unknown. Here, we reveal that PKA phosphorylates the type III IP3 receptor at Ser916, Ser934 and Ser1832, and that, intriguingly, each site is located close to a putative surface-exposed peptide loop. Furthermore, we demonstrate that Ser934 is considerably more susceptible to PKA-dependent phoshorylation than either Ser916 or Ser1832. 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.
Soulsby
Matthew D
MD
Department of Pharmacology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210-2339, USA.
Wojcikiewicz
Richard J H
RJ
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D015220:Calcium Channels / Q000378:metabolism*; D020013:Calcium Signaling; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
D015220:Calcium Channels; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D017868:Cyclic AMP-Dependent Protein Kinases