Biochemistry, Dopamine Receptors

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 Level

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 the kidney and vasculature,

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

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, memory, fear, 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, and 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, and D5, and the least abundant is D4. D1 receptors help regulate the development of neurons when the dopamine hormone binds to them.

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 the 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 a decreased 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]:

• 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.
• 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