Association of Type 1 Inositol 1,4,5-Trisphosphate Receptor with AKAP9 (Yotiao) and Protein Kinase A

Huiping Tu, Tie Shan Tang, Zhengnan Wang, Ilya Bezprozvanny

Research output: Contribution to journalArticle

63 Citations (Scopus)

Abstract

Inositol 1,4,5-trisphosphate receptors (InsP3R) play a key role in intracellular calcium (Ca2+) signaling. Three InsP3R isoforms are expressed in mammals. Type 1 InsP3R (InsP3R1) is a predominant neuronal isoform. Neuronal InSP3R1 is one of the major substrates of protein kinase A (PKA) phosphorylation. In our previous study (Tang, T. S., Tu, H., Wang, Z., and Bezprozvanny, I. (2003) J. Neurosci. 23, 403-415) we discovered a direct association between InSP3R1 and protein phosphatase 1α (PP1α). In functional experiments we demonstrated that phosphorylation by PKA activates InsP3R1 and that dephosphorylation by PP1α inhibits InSP3R1. To extend these findings, here we investigated the possibility of InsP3R1-PKA association. In a series of biochemical experiments we demonstrate the following findings. 1) InsP3R1 and PKA associate in the brain. 2) InsP3R1-PKA association is mediated by the AKAP9 (Yotiao) multifunctional PKA anchoring protein. 3) InsP3R1-AKAP9 association is mediated via the leucine/isoleucine zipper (LIZ) motif in the InSP 3R1 coupling domain and the fourth LIZ motif in AKAP9. 4) The InSP3R association with AKAP9 is specific for type 1 InsP 3R. 5) Both the SII(+) and the SII(-) coupling domain splice variants of InsP3R1 bind to AKAP9. 6) Binding to AKAP9 promotes association of neuronal InSP3R1 with the NR1 NMDA receptor; and 7) neuronal InSP3R1 associate with PP1 directly via carboxy-terminus and indirectly via AKAP9. The obtained results advance our understanding of cross-talk between cAMP and InsP3/Ca2+ signaling pathways in the brain.

Original languageEnglish (US)
Pages (from-to)19375-19382
Number of pages8
JournalJournal of Biological Chemistry
Volume279
Issue number18
DOIs
StatePublished - Apr 30 2004

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Inositol 1,4,5-Trisphosphate Receptors
Cyclic AMP-Dependent Protein Kinases
Association reactions
Protein Phosphatase 1
Leucine Zippers
Phosphorylation
Isoleucine
Fasteners
Leucine
Brain
Protein Isoforms
Mammals
Calcium Signaling
Experiments
Calcium
Substrates
Proteins

ASJC Scopus subject areas

  • Biochemistry

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Association of Type 1 Inositol 1,4,5-Trisphosphate Receptor with AKAP9 (Yotiao) and Protein Kinase A. / Tu, Huiping; Tang, Tie Shan; Wang, Zhengnan; Bezprozvanny, Ilya.

In: Journal of Biological Chemistry, Vol. 279, No. 18, 30.04.2004, p. 19375-19382.

Research output: Contribution to journalArticle

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abstract = "Inositol 1,4,5-trisphosphate receptors (InsP3R) play a key role in intracellular calcium (Ca2+) signaling. Three InsP3R isoforms are expressed in mammals. Type 1 InsP3R (InsP3R1) is a predominant neuronal isoform. Neuronal InSP3R1 is one of the major substrates of protein kinase A (PKA) phosphorylation. In our previous study (Tang, T. S., Tu, H., Wang, Z., and Bezprozvanny, I. (2003) J. Neurosci. 23, 403-415) we discovered a direct association between InSP3R1 and protein phosphatase 1α (PP1α). In functional experiments we demonstrated that phosphorylation by PKA activates InsP3R1 and that dephosphorylation by PP1α inhibits InSP3R1. To extend these findings, here we investigated the possibility of InsP3R1-PKA association. In a series of biochemical experiments we demonstrate the following findings. 1) InsP3R1 and PKA associate in the brain. 2) InsP3R1-PKA association is mediated by the AKAP9 (Yotiao) multifunctional PKA anchoring protein. 3) InsP3R1-AKAP9 association is mediated via the leucine/isoleucine zipper (LIZ) motif in the InSP 3R1 coupling domain and the fourth LIZ motif in AKAP9. 4) The InSP3R association with AKAP9 is specific for type 1 InsP 3R. 5) Both the SII(+) and the SII(-) coupling domain splice variants of InsP3R1 bind to AKAP9. 6) Binding to AKAP9 promotes association of neuronal InSP3R1 with the NR1 NMDA receptor; and 7) neuronal InSP3R1 associate with PP1 directly via carboxy-terminus and indirectly via AKAP9. The obtained results advance our understanding of cross-talk between cAMP and InsP3/Ca2+ signaling pathways in the brain.",
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