Biochemistry, Dopamine Receptors


Article Author:
Anmol Bhatia


Article Editor:
Abdolreza Saadabadi


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Updated:
2/25/2019 6:38:49 PM

Introduction

Cell to cell communication is critical for the survival of an organism. Cells can communicate through a process called signal transduction pathway. When sending a signal, different molecules, such as hormones, can bind to a receptor on or inside the cell membrane, leading to chemical reactions in the cell ultimately reaching the target. Cells use a second messenger to transmit these messages. 

This article will be discussing the different types of receptors, focusing specifically on dopamine receptors, the different types of dopamine receptors, and what function each receptor has. The article will also go into different illnesses and medications that target these receptors. The dopamine receptors affect many various functions, ranging from hypertension and hormonal regulation to voluntary movement and reward.[1]

Fundamentals

There are many different types of signaling receptors in the human body, with the majority being the G-protein coupled receptors (GPCRs). GPCRs have an intracellular C-terminus and an extracellular N-terminus. GPCRs are also known as the seven-pass transmembrane proteins; this is because the receptor consists of seven sequential helices that cross the transmembrane, allowing the receptor to correctly insert into the cell membrane and couple with the G protein. This coupling permits the receptor to modulate signaling cascades.  The dopamine receptor is a type of G-protein coupled receptor. Dopamine receptors can also act through G-protein independent mechanisms such as ion channel interactions. 

Dopamine is a monoamine catecholamine neurotransmitter and hormone. It binds to the dopamine receptor, and depending on the type of receptor, has many different functions. Dopamine receptors are mostly present in the central nervous system.[2]

Cellular

The dopamine receptors are located and encoded by different genes. D1 receptor encoding is by the gene, 5q31-q34. The D2 receptor is on chromosome 11, along with the D4 receptor, while the D3 receptor is located on the third chromosome. The D5 receptor is on the fourth chromosome.[2][3]

Function

Dopamine receptors play an essential role in daily life functions. This hormone and its receptors affect movement, emotions and the reward system in the brain.

Dopamine receptors are expressed in the central nervous system, specifically in the hippocampal dentate gyrus and subventricular zone. Dopamine receptors are also expressed in the periphery, more prominently in kidney and vasculature,

There are five types of dopamine receptors, which include D1, D2, D3, D4, and D5. Each receptor has a different function.

The function of each dopamine receptor[4]:

  • D1: memory, attention, impulse control, regulation of renal function, locomotion
  • D2: locomotion, attention, sleep, memory, learning
  • D3: cognition, impulse control, attention, sleep
  • D4: cognition, impulse control, attention, sleep
  • D5: decision making, cognition, attention, renin secretion

Pathophysiology

The five different dopamine receptors can subdivide into two categories. D1 and D5 receptors group together, and D2, D3, D4 are together in a separate subgrouping. 

D1 and D5 receptors couple to G stimulatory sites and activate adenylyl cyclase. The activation of adenylyl cyclase leads to the production of the second messenger cAMP, which leads to the production of protein kinase A (PKA) which leads to further transcription in the nucleus.  

D2 through D4 receptors couple to G inhibitory sites, which inhibit adenylyl cyclase and activate K+ channels. 

The D1 receptor is the most abundant out of the five in the central nervous system, followed by D2, then D3, D5 and least abundant is D4. D1 receptors help regulate the development of neurons when the dopamine hormone binds to it.

D1 and D5 receptors have high density in the striatum, nucleus accumbens, olfactory bulb, and substantia nigra. These receptors are essential in regulating the reward system, motor activity, memory, and learning. D1 and D5 receptors, along with stimulating adenyl cyclase, also activate phospholipase C, which leads to the induction of intracellular calcium release and activation of protein kinase C. Protein kinase C is a calcium-dependent protein kinase. Calcium is also involved in modulating neurotransmitter release by exocytosis. D1 and D5 receptors are also involved in the kidney by inhibiting Na/K ATPase through PKA and PKC pathways. In the kidney, these receptors correlate with an increase in electrolyte excretion and renal vasodilation.

D2, D3, and D4 receptors are expressed mainly in the striatum, as well as the external globus pallidus, core of nucleus accumbens, hippocampus, amygdala, and cerebral cortex.  These receptors also affect the postsynaptic receptor-medicated extrapyramidal activity. D2-D4 receptors are important in the signaling for the survival of human dopamine neurons and neuronal development.[4][5]

Clinical Significance

Many different diseases involve increased or decreased dopamine leading to different effects. The two primary conditions discussed here along with the pharmacology targeting dopamine receptors are Parkinson disease and schizophrenia.

Parkinson disease[6][7]:

  • A disease caused by decrease amount of dopamine in the substantia nigra (in the nigrostriatal pathway)
  • Symptoms include resting tremor, bradykinesia, shuffling gait, postural instability
  • Treatment for Parkinson disease includes medications that target to increase dopamine availability
    • Bromocriptine is a D2 receptor agonist; other dopamine agonists include pramipexole and ropinirole
    • Amantadine increases dopamine availability by increasing the release of dopamine and decreasing reuptake
    • Carbidopa and levodopa are commonly used together; in the CNS levodopa is converted into dopamine to increase the amount of dopamine in the CNS and carbidopa inhibits DOPA decarboxylase, which blocks the peripheral conversion of levodopa to dopamine - this decreases the peripheral side effects of dopamine
    • Other medications, such as selegiline and tolcapone inhibit the breakdown of dopamine, which increases the availability at the synapse

Schizophrenia[8][9][10][9][8]:

  • Associated with an increase in dopaminergic activity
  • Genetic and environmental risk factors affect the dopamine function
  • Diagnosis includes greater than 6 months of at least 2 of the following: delusions, disorganized speech, hallucinations, disorganized behavior, and negative symptoms (anhedonia, flat affect, etc.), and at least one of the symptoms needs to be hallucinations, delusions, or disorganized speech
  • Treatment for schizophrenia includes medications that target to decrease dopamine availability, which includes atypical and typical antipsychotics
    • Typical antipsychotics are also known as first-generation antipsychotics - these drugs block the D2 receptor
      • High potency typical antipsychotics include haloperidol, trifluoperazine, and fluphenazine
      • Low potency typical antipsychotics include chlorpromazine and thioridazine.
  • The atypical antipsychotics have unique characteristics
    • Most are D2 antagonists and also affect other receptors, such as the serotonin and histamine receptors; aripiprazole is D2 partial agonist
    • Atypical antipsychotics bind more loosely to the dopamine D2 receptor than the typical antipsychotics

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Biochemistry, Dopamine Receptors - Questions

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Which of the following dopamine receptors stimulates adenylate cyclase?



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Which of the following is encoded by the 5q31-q34 gene?



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A 60-year-old male presents to his primary care provider complaining of a resting tremor. The male has a shuffling gait and bradykinesia. The clinical diagnosis of Parkinson disease is made. The patient is started on bromocriptine, a D2 receptor agonist. Which of the following is true about this receptor?



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Which dopamine receptors is the most abundant in the central nervous system?



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A 26-year-old male presented to the ED with his mother stating he sees dogs in the hospital room and hears voices of angels. The mother states he has been paranoid thinking the TV is sending him messages and making these comments for the past 7 months. The clinician prescribes him a medication that should help control these hallucinations. He states this is a typical antipsychotic. What receptor is the medication targeting and is it an antagonist or agonist?



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Biochemistry, Dopamine Receptors - References

References

Beaulieu JM,Espinoza S,Gainetdinov RR, Dopamine receptors - IUPHAR Review 13. British journal of pharmacology. 2015 Jan;     [PubMed]
Mishra A,Singh S,Shukla S, Physiological and Functional Basis of Dopamine Receptors and Their Role in Neurogenesis: Possible Implication for Parkinson's disease. Journal of experimental neuroscience. 2018;     [PubMed]
Seeman P, An update of fast-off dopamine D2 atypical antipsychotics. The American journal of psychiatry. 2005 Oct;     [PubMed]
Vekshina NL,Anokhin PK,Veretinskaya AG,Shamakina IY, [Heterodimeric D1-D2 dopamine receptors: a review]. Biomeditsinskaia khimiia. 2017 Jan;     [PubMed]
Tardy M,Huhn M,Engel RR,Leucht S, Fluphenazine versus low-potency first-generation antipsychotic drugs for schizophrenia. The Cochrane database of systematic reviews. 2014 Aug 3;     [PubMed]
Howes OD,McCutcheon R,Owen MJ,Murray RM, The Role of Genes, Stress, and Dopamine in the Development of Schizophrenia. Biological psychiatry. 2017 Jan 1;     [PubMed]
Gilat M,Bell PT,Ehgoetz Martens KA,Georgiades MJ,Hall JM,Walton CC,Lewis SJG,Shine JM, Dopamine depletion impairs gait automaticity by altering cortico-striatal and cerebellar processing in Parkinson's disease. NeuroImage. 2017 May 15;     [PubMed]
You H,Mariani LL,Mangone G,Le Febvre de Nailly D,Charbonnier-Beaupel F,Corvol JC, Molecular basis of dopamine replacement therapy and its side effects in Parkinson's disease. Cell and tissue research. 2018 Jul;     [PubMed]
Grandy DK,Litt M,Allen L,Bunzow JR,Marchionni M,Makam H,Reed L,Magenis RE,Civelli O, The human dopamine D2 receptor gene is located on chromosome 11 at q22-q23 and identifies a TaqI RFLP. American journal of human genetics. 1989 Nov;     [PubMed]
Grandy DK,Allen LJ,Zhang Y,Magenis RE,Civelli O, Chromosomal localization of three human D5 dopamine receptor genes. Genomics. 1992 Aug;     [PubMed]

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