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Neurophysiological process_Glutamate regulation of Dopamine D1A receptor signaling
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, <endoplasmic reticulum> Ca('2+) = <cytosol> Ca('2+), GABA-A receptor beta-2 subunit, mGluR1, <extracellular region> Ca('2+) = <cytosol> Ca('2+), PP1-cat, GABA-A receptor beta-3 subunit, PP2A catalytic, Striatin, CDK5, G-protein alpha-q, PLC-beta1, ATP, DARPP-32, Calcineurin A (catalytic), Casein kinase I epsilon, Ca('2) cytosol, SG2NA, Calcineurin B (regulatory), PtdIns(4,5)P2,, Dopamine D1A receptor, CDK5R1 (p35),, PKA-reg (cAMP-dependent), G-protein alpha-s, CREB1, Dopamine extracellular region, Ca('2+) extracellular region, (L)-Glutamic acid extracellular region


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 [1].

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 [2], [3] and/or protein Phosphatase 1, regulatory subunit 1A ( IPP-1 ) at Thr 35 [4]. Thr 35-phosphorylated IPP-1 and Thr 34-phosphorylated DARPP-32 inhibit Protein phosphatase1 catalytic subunit ( PP1-cat ) [4], [3].

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 ) [5] and/or cAMP responsive element binding protein 1 ( CREB1 ) [6].

It is shown, that Glutamic acid may regulate Dopamine D1A receptor signaling via multiple receptors, e.g., Glutamate receptor, metabotropic 1 ( mGluR1) [6] , Glutamate receptor ionotropic N-methyl D-aspartate ( NMDA ) and Glutamate receptor ionotrophic AMPA ( AMPA ) [7]. 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 [8]. NMDA and AMPA activate Ca2+ transport from extracellular region to cytosol [7]. Cytosol Ca 2+ activates Protein phosphatase 3 ( Calcineurin ) [7], [8]/

Calcineurin dephosphorylates inhibitory autophosphorylation sites of Casein Kinase I epsilon resulting in its activation [8]. Casein Kinase I epsilon activates cyclin-dependent kinase 5 regulatory subunit 1 ( CDK5R1(p35 ))/ Cyclin-dependent kinase 5 ( CDK5 ) [4]. CDK5, in turn, stimulates the phosphorylation of DARPP-32 at Thr-75 [2], [9] and IPP-1 at Ser 67 [10]. DARPP-32 phosphorylated at Thr 75 inhibits PKA. IPP-1 phosphorylated at Ser 67 does not inhibit PP1-cat [10]. 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 [10]. It leads to inhibit of PP-1cat.

In addition, Calcineurin may dephosphorylate DARPP-32 at Thr 34 [11], [7]. It leads to activation 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 ) [12], [7]. PP2A directly dephosphorylates DARPP-32 at Thr 75 [11], [7] and IPP-1 at Ser 67 [10]. The latter leads to activation of PP-1 cat.


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    DARPP-32 Is a Robust Integrator of Dopamine and Glutamate Signals. PLoS computational biology 2006 Dec 22;2(12):e176
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    Phosphorylation of DARPP-32 by Cdk5 modulates dopamine signalling in neurons. Nature 1999 Dec 9;402(6762):669-71
  3. Bibb JA
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    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
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    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
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    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
  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
  10. 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
  11. 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
  12. 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