D2

links: GPCR reference:

• Dopamine in neurotoxicity and neuroprotection: what do D2 receptors have to do with it? https://sci-hub.st/https://doi.org/10.1016/j.tins.2006.01.002
• Multiple receptors for dopamine: https://www.nature.com/articles/277093a0 8-16-2021

D2 #

• There are three isoforms: (And the ‘D2 family’ also consists of D3 and D4.)
  • D2Sh (short) is pre-synaptic and an autoreceptor.
    • Regulates presynaptic DA storage/synthesis/release, with agonism inhibiting DA release.
  • D2Lh (long) is a post-synaptic receptor, just canonical old Gαi.
  • There’s also a ’longer’ isoform.
• There’s also D2 ‘high’ and D2 ’low’ conformational states (‘conformers’) when complexed with an agonist and antagonist respectively.
• Midlet says D2 generates reward by increasing urges for perfectionism. Its inhibitory nature is basically analogous to trying to step 10 meters in one step. In a way, they’re responsible for the search for novetly as it taints the mundane activities as boring.
• At rest, ~85-90% of them are unbound to DA.
• Inhibits Lactotrophs.
• Promotes DAT surface expression via Protein Kinase Cβ2.
• The DRD2 TaqI polymorphism and symptoms of attention deficit hyperactivity disorder: We doubt that this DRD2 polymorphism influences symptoms of ADHD in childhood.
• Thinking Outside a Less Intact Box: Thalamic Dopamine D2 Receptor Densities Are Negatively Related to Psychometric Creativity in Healthy Individuals
• https://men-elite.com/2020/01/03/the-high-dopamine-histamine-personality/
  • Postsynaptic D2 suppresses Glutamatergic transmission … through endocanabinoid signaling. Presynaptic D2 suppresses glutamatergic transmission through endocannabinoid independent signalling.
• Altered dopaminergic profile in the putamen and substantia nigra in restless leg syndrome
  • (Severe?) restless leg syndrome tissue (substantia nigra and putamen autopsy) showed a significant decrease in D2.
• An Akt/β-Arrestin 2/PP2A Signaling Complex Mediates Dopaminergic Neurotransmission and Behavior
  • Activation of D2-class results in a reduction of AKT activity. Increase in (striatal) cAMP or PP2B inhibition did not affect AKT/GSK-3β (as one would expect) so it’s a novel mechanism - they conclude one which involves β-Arrestin.
• Correlation between striatal dopamine D2/D3 receptor binding and cardiovascular activity in healthy subjects
• Thinking Outside a Less Intact Box: Thalamic Dopamine D2 Receptor Densities Are Negatively Related to Psychometric Creativity in Healthy Individuals
  • Scores on divergent thinking were correlated with regional D2 densities - but negatively in the thalamus.

Cannabinoid #

• [Frequency-specific and D2 receptor-mediated inhibition of glutamate release by retrograde endocannabinoid]
  • D2 inhibits striatal glutamate release via retrograde endocannabinoid signaling!
    • [A critical interaction between dopamine D2 receptors and endocannabinoids mediates the effects of cocaine on striatal gabaergic transmission]
      • Cocaine, via activating D2-like, increases the levels of Anandamide in the striatum.
      • Cocaine, but not morphine, induces conditioned place preference and sensitization to locomotor responses in CB1 knockout mice. (2008) i.e. CB1 knockout abolished morphine’s rewarding effects!? According to the study. Related:
        • Behavioural and biochemical responses to morphine associated with its motivational properties are altered in adenosine A2A receptor knockout mice (2009)
          • The rewarding effects induced by morphine were completely blocked in A2A KO mice. Also, naloxone did not induce place aversion in animals lacking the A2ARs.
        • Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice
          • The acute effects were unaffected, but the reinforcing properties of morphine and the severity of the withdrawal syndrome were strongly reduced.
      • CB1 cannabinoid receptor antagonist-induced opiate withdrawal in morphine-dependent rats.

Structure #

• Monomeric. 6 domains/subunits.
• Dopamine D2 receptors form higher order oligomers at physiological expression levels
• Dysregulation of Dopamine Transporters via Dopamine D2 Autoreceptors Triggers Anomalous Dopamine Efflux Associated with Attention-Deficit Hyperactivity Disorder
  • A559V is a DAT coding variant, resulting in efflux. Amphetamine/Methylphenidate block this. I don’t get it - how does this not augment attention?