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. 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.

References:

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