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) [3], [4].

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 Ca²⁺ 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 Ca²⁺ 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 [7], [11]. 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) [7], [12]. PP2A directly dephosphorylates DARPP-32 at Thr 75 [7], [11] and IPP-1 at Ser 67 [10]. The latter leads to activation of PP-1 cat.

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