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Neurophysiological process Glutamate regulation of Dopamine D1A receptor signaling

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Neurophysiological process Glutamate regulation of Dopamine D1A receptor signaling

Glutamic acid regulation of Dopamine D1A receptor signaling

Glutamic acid is the major excitatory neurotransmitter in the brain. Theexcitation of medium spiny neurons is regulated by a balance of glutamatergic inputs fromcorticostriatal and thalamostriatal pathways and dopaminergic inputs from thenigrostriatal pathway [1].

Dopamine D1A receptor signaling cascade, that contains a specific Guaninenucleotide binding protein GNAS complex locus ( G-protein alpha-s )/ Adenylatecyclase type V/ Cyclic adenosine monophosphate ( cAMP ), activatescAMP-dependent protein kinase ( PKA ). PKA phosphorylates DARPP-32at Thr 34 [2], [3] and/or protein Phosphatase 1, regulatorysubunit 1A ( IPP-1 ) at Thr 35 [4]. Thr 35-phosphorylatedIPP-1 and Thr 34-phosphorylated DARPP-32 inhibit Protein phosphatase1catalytic subunit ( PP1-cat ) [4], [3].

PKA and PP1-cat regulate the phosphorylation state and activity of manyphysiological effectors, including neurotransmitter receptors that regulate excitabilityof medium spiny neurons. PP-1 inhibition and/or PKA activation may lead tostimulation 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 receptorsignaling via multiple receptors, e.g., Glutamate receptor, metabotropic 1 (mGluR1A) [6] , Glutamate receptor ionotropic N-methylD-aspartate ( NMDA ) and Glutamate receptor ionotrophic AMPA ( AMPA )[7]. All three receptors raise cytosolic Ca 2+ level.mGluR1A 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 fromextracellular region to cytosol [7]. Cytosol Ca 2+activates Protein phosphatase 3 ( Calcineurin ) [7], [8]/

Calcineurin dephosphorylates inhibitory autophosphorylation sites of CaseinKinase I epsilon resulting in its activation [8]. Casein Kinase Iepsilon 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 atThr 75 inhibits PKA. IPP-1 phosphorylated at Ser 67 does notinhibit PP1-cat [10]. This leads to activation of PP-1cat andsynergistically 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 intracellularCa2+. This stimulates Protein phosphatase 2 ( PP2A ), possibly viaCalmodulin/ Striatin calmodulin binding proteins ( Striatin andSG2NA ) [12], [7]. PP2A directly dephosphorylatesDARPP-32 at Thr 75 [11], [7] and IPP-1 at Ser 67[10]. The latter leads to activation of PP-1 cat.