Pathway Map Details
Neurophysiological process_Glutamate regulation of Dopamine D1A receptor signaling
Object list (links open in MetaCore):
Adenylate cyclase type V, DARPP-32, NMDA receptor, IPP-1, cAMP, Ca('2+) endoplasmic reticulum lumen, AMPA receptor, Calmodulin, GABA-A receptor beta-1 subunit, IP3 receptor, DAG, PLC-beta2, IP3, PP2A structural, PKA-cat (cAMP-dependent), PP2A regulatory,
Glutamic acid regulation of Dopamine D1A receptor signaling
Glutamic acid is the major excitatory neurotransmitter in the brain. The excitation of medium spiny neurons is regulated by a balance of glutamatergic inputs from corticostriatal and thalamostriatal pathways and dopaminergic inputs from the nigrostriatal pathway .
Dopamine D1A receptor signaling cascade, that contains a specific Guanine nucleotide binding protein GNAS complex locus ( G-protein alpha-s )/ Adenylate cyclase type V/ Cyclic adenosine monophosphate ( cAMP ), activates cAMP-dependent protein kinase ( PKA ). PKA phosphorylates DARPP-32 at Thr 34 ,  and/or protein Phosphatase 1, regulatory subunit 1A ( IPP-1 ) at Thr 35 . Thr 35-phosphorylated IPP-1 and Thr 34-phosphorylated DARPP-32 inhibit Protein phosphatase1 catalytic subunit ( PP1-cat ) , .
PKA and PP1-cat regulate the phosphorylation state and activity of many physiological effectors, including neurotransmitter receptors that regulate excitability of medium spiny neurons. PP-1 inhibition and/or PKA activation may lead to stimulation of Gamma-aminobutyric acid (GABA) A receptor ( GABA-A receptor )  and/or cAMP responsive element binding protein 1 ( CREB1 ) .
It is shown, that Glutamic acid may regulate Dopamine D1A receptor signaling via multiple receptors, e.g., Glutamate receptor, metabotropic 1 ( mGluR1)  , Glutamate receptor ionotropic N-methyl D-aspartate ( NMDA ) and Glutamate receptor ionotrophic AMPA ( AMPA ) . All three receptors raise cytosolic Ca 2+ level. mGluR1 activates a cascade that composes of G-protein alpha-q/ Phospholipase C, beta 1 ( PLC beta 1 )/ Inositol 1,4,5-trisphosphate ( IP3 ). This cascade activates Ca2+ transport from endoplasmic reticulum to cytosol . NMDA and AMPA activate Ca2+ transport from extracellular region to cytosol . Cytosol Ca 2+ activates Protein phosphatase 3 ( Calcineurin ) , /
Calcineurin dephosphorylates inhibitory autophosphorylation sites of Casein Kinase I epsilon resulting in its activation . Casein Kinase I epsilon activates cyclin-dependent kinase 5 regulatory subunit 1 ( CDK5R1(p35 ))/ Cyclin-dependent kinase 5 ( CDK5 ) . CDK5, in turn, stimulates the phosphorylation of DARPP-32 at Thr-75 ,  and IPP-1 at Ser 67 . DARPP-32 phosphorylated at Thr 75 inhibits PKA. IPP-1 phosphorylated at Ser 67 does not inhibit PP1-cat . This leads to activation of PP-1cat and synergistically reduces phosphorylation of its various common substrates.
Ser 67-phosphorylated IPP-1 may be dephosphorylated by Calcineurin . It leads to inhibit of PP-1cat.
Moreover, Glutamic acid via NMDA and AMPA raise intracellular Ca2+. This stimulates Protein phosphatase 2 ( PP2A ), possibly via Calmodulin/ Striatin calmodulin binding proteins ( Striatin and SG2NA ) , . PP2A directly dephosphorylates DARPP-32 at Thr 75 ,  and IPP-1 at Ser 67 . The latter leads to activation of PP-1 cat.
- Fernandez E, Schiappa R, Girault JA, Novere NL
DARPP-32 Is a Robust Integrator of Dopamine and Glutamate Signals. PLoS computational biology 2006 Dec 22;2(12):e176
- Bibb JA, Snyder GL, Nishi A, Yan Z, Meijer L, Fienberg AA, Tsai LH, Kwon YT, Girault JA, Czernik AJ, Huganir RL, Hemmings HC Jr, Nairn AC, Greengard P
Phosphorylation of DARPP-32 by Cdk5 modulates dopamine signalling in neurons. Nature 1999 Dec 9;402(6762):669-71
- Bibb JA
Role of Cdk5 in neuronal signaling, plasticity, and drug abuse. Neuro-Signals 2003 Sep-Oct;12(4-5):191-9
- Liu F, Ma XH, Ule J, Bibb JA, Nishi A, DeMaggio AJ, Yan Z, Nairn AC, Greengard P
Regulation of cyclin-dependent kinase 5 and casein kinase 1 by metabotropic glutamate receptors. Proceedings of the National Academy of Sciences of the United States of America 2001 Sep 25;98(20):11062-8
- Flores-Hernandez J, Hernandez S, Snyder GL, Yan Z, Fienberg AA, Moss SJ, Greengard P, Surmeier DJ
D(1) dopamine receptor activation reduces GABA(A) receptor currents in neostriatal neurons through a PKA/DARPP-32/PP1 signaling cascade. Journal of neurophysiology 2000 May;83(5):2996-3004
- Svenningsson P, Nishi A, Fisone G, Girault JA, Nairn AC, Greengard P
DARPP-32: an integrator of neurotransmission. Annual review of pharmacology and toxicology 2004;44:269-96
- Nishi A, Bibb JA, Matsuyama S, Hamada M, Higashi H, Nairn AC, Greengard P
Regulation of DARPP-32 dephosphorylation at PKA- and Cdk5-sites by NMDA and AMPA receptors: distinct roles of calcineurin and protein phosphatase-2A. Journal of neurochemistry 2002 May;81(4):832-41
- Liu F, Virshup DM, Nairn AC, Greengard P
Mechanism of regulation of casein kinase I activity by group I metabotropic glutamate receptors. The Journal of biological chemistry 2002 Nov 22;277(47):45393-9
- Nishi A, Watanabe Y, Higashi H, Tanaka M, Nairn AC, Greengard P
Glutamate regulation of DARPP-32 phosphorylation in neostriatal neurons involves activation of multiple signaling cascades. Proceedings of the National Academy of Sciences of the United States of America 2005 Jan 25;102(4):1199-204
- Bibb JA, Nishi A, O'Callaghan JP, Ule J, Lan M, Snyder GL, Horiuchi A, Saito T, Hisanaga S, Czernik AJ, Nairn AC, Greengard P
Phosphorylation of protein phosphatase inhibitor-1 by Cdk5. The Journal of biological chemistry 2001 Apr 27;276(17):14490-7
- Nishi A, Snyder GL, Nairn AC, Greengard P
Role of calcineurin and protein phosphatase-2A in the regulation of DARPP-32 dephosphorylation in neostriatal neurons. Journal of neurochemistry 1999 May;72(5):2015-21
- Moreno CS, Park S, Nelson K, Ashby D, Hubalek F, Lane WS, Pallas DC
WD40 repeat proteins striatin and S/G(2) nuclear autoantigen are members of a novel family of calmodulin-binding proteins that associate with protein phosphatase 2A. The Journal of biological chemistry 2000 Feb 25;275(8):5257-63