Dopamine and its receptor

Dopamine and its receptor

The neurotransmitter dopamine is the primary endogenous ligand for dopamine receptors. Dopamine receptors are a class of metabotropic G protein-coupled receptors that are prominent in the vertebrate central nervous system (CNS).

Biosynthesis of Dopamine

Dopamine, a catecholamine, is synthesized in the terminals of dopaminergic neurons from tyrosine, which is transported across the blood-brain barrier by an active process. The rate-limiting step in the synthesis of dopamine is the conversion of L-tyrosine to L-dihydroxyphenylalanine (L-DOPA), catalyzed by the enzyme tyrosine hydroxylase. L-DOPA is converted rapidly to dopamine by aromatic L-amino acid decarboxylase.

Fig. 1 Dopaminergic terminal.

Location

CNS- Assays of distinct regions of the CNS eventually revealed that the distributions of dopamine and norepinephrine are markedly different. In fact, more than half the CNS content of catecholamine is dopamine and extremely large amounts are found in the basal ganglia, the nucleus accumbens, the olfactory tubercle, the central nucleus of the amygdala, the median eminence, and restricted fields of the frontal cortex.

Cardio-pulmonary- In humans, the pulmonary artery expresses D1, D2, D4, and D5 and receptor subtypes, which may account for vasorelaxive effects of dopamine in the blood. In rats, D1-like receptors are present on the smooth muscle of the blood vessels in most major organs.

D4 receptors have been identified in the atria of rat and human hearts. Dopamine increases myocardial contractility and cardiac output, without changing heart rate, by signaling through dopamine receptors.

Renal- Dopamine receptors are present along the nephron in the kidney, with proximal tubule epithelial cells showing the highest density. In rats, D1-like receptors are present on the juxtaglomerular apparatus and on renal tubules, while D2-like receptors are present on the renal tubules, glomeruli, postganglionic sympathetic nerve terminals, and zona glomerulosa cells of the renal cortex. Dopamine signaling affects diuresis and natriuresis.

Storage and release

In dopaminergic nerve terminals, dopamine is taken up into vesicles by a transporter protein; this process is blocked by reserpine, which leads to depletion of dopamine. Release of dopamine from nerve terminals occurs through exocytosis of presynaptic vesicles, a process that is triggered by depolarization leading to entry of Ca2+. Release, triggered by depolarization and entry of Ca2+, allows dopamine to act on postsynaptic dopamine receptors (DAR).

Metabolism

Once dopamine is in the synaptic cleft, its actions may be terminated by reuptake through a membrane carrier protein, a process antagonized by drugs such as cocaine. Alternatively, dopamine can be degraded by the sequential actions of monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT) to yield two metabolic products, 3,4-dihydroxyphenylacetic acid (DOPAC) and 3-methoxy-4-hydroxyphenylacetic acid (HVA). In human beings, HVA is the primary product of the metabolism of dopamine

Dopamine receptors

Dopamine receptors have key roles in many processes, including the control of motivation, learning, and fine motor movement, as well as modulation of neuroendocrine signaling. Abnormal dopamine receptor signaling and dopaminergic nerve function is implicated in several neuropsychiatric disorders. Thus, dopamine receptors are common neurologic drug targets.

Antipsychotics- dopamine receptor antagonists while psychostimulants- indirect agonists of dopamine receptors. At the cellular level, the actions of dopamine depend on receptor subtype expression.

The dopamine receptors share several structural features, including the presence of seven alpha-helical segments capable of spanning the cell membrane. This structure identifies the dopamine receptors as members of the larger superfamily of seven-transmembrane-region receptor proteins. All members of this superfamily act through guanine nucleotide-binding proteins.

The actions of dopamine in the brain are mediated by a family of dopamine receptor proteins. Two types of dopamine receptors were identified in the mammalian brain using pharmacological techniques:

D1 receptors family, which stimulate the synthesis of the intracellular second messenger cyclic AMP, and

D2 receptors family, which inhibit cyclic AMP synthesis.

The five dopamine receptors can be divided into two groups on the basis of their pharmacological and structural properties (Fig. 2).

SNpc, substantia nigra pars compacta; cAMP-cyclic AMP; psi-voltage.

Fig. 2 Distribution and characteristics of dopamine receptors.

D1-like family (excitatory)

The D1 and D5 proteins have a long intracellular carboxy-terminal tail and are members of the pharmacologically defined D1 class. Activation of the D1-like family receptors is coupled to the G protein Gαs, which subsequently activates adenylyl cyclase, increasing the intracellular concentration of the second messenger Cyclic adenosine monophosphate (cAMP). Increased cAMP in neurons is typically excitatory and can induce an action potential by modulating the activity of ion channels.

D2-like family (inhibitory)

The D2, D3, and D4 receptors share a large third intracellular loop and are of the D2 class. D2-like activation is coupled to the G protein Gαi, which subsequently increased phosphodiesterase activity. Phosphodiesterases break down cAMP, producing an inhibitory effect in neurons. They decrease cyclic AMP formation and modulate K+ and Ca2+ currents.

D1-like receptor agonists

Fenoldopam, Piribedil, Ibopamine, SKF 3893, Apomorphine

Therapeutic uses of D1-like receptor agonists

* Decreases peripheral resistance

* Inducing lowering of arterial blood pressure-increases in heart rate and increases in sympathetic tone

* Increases in activity of the rennin-aldosterone system

D2-like receptor agonists

Bromocriptine, Pergolid, Lisuride, Guinpirole, Carmoxirole

Therapeutic uses of D2-like receptor agonists

* Used for treating Parkinson’s disease

* Inhibits prolactin release (which decreases tumor size)

D1-like receptor antagonists

SCH23390, Clozapine (used for treating schizophrenia)

D2-like receptor antagonists

Metoclopramid, Domperidone (Gastric Motility Disorders), Sulpiride, Haloperidol,

Dopamine receptors in disease

Dysfunction of dopaminergic neurotransmission in the CNS has been implicated in a variety of neuropsychiatric disorders, including Tourette's syndrome (inherited neurological disorders- tic disorder (involuntary movement), Parkinson's disease, schizophrenia, Attention-deficit hyperactivity disorder (ADHD), and drug and alcohol dependence.

Attention-deficit hyperactivity disorder

Dopamine receptors have been recognized as important components in the etiology of ADHD for many years. Drugs used to treat ADHD, including methylphenidate and amphetamine, have significant effects on dopamine signaling in the brain. Studies of gene association have implicated several genes within dopamine signaling pathways; in particular, the D4.7 variant of D4 has been consistently shown to be more frequent in ADHD patients. The D4.7 allele has suppressed gene expression compared to other variants.

Drug abuse

Dopamine is the primary neurotransmitter involved in the reward pathways in the brain. Thus, drugs that increase dopamine signaling may produce euphoric effects. Cocaine and methamphetamine—two examples of such drugs—alter the functionality of the dopamine transporter (DAT), the protein responsible for removing dopamine from the neural synapse. When DAT activity is blocked, the synapse floods with dopamine and increases dopaminergic signaling. When this occurs, particularly in the nucleus accumbens, increased D1 and D2 receptor signaling mediates the "rewarding" stimulus of drug intake.

Schizophrenia

While there is evidence that the dopamine system is involved in schizophrenia, the theory that hyperactive dopaminergic signal transduction induces the disease is controversial. Psychostimulants, such as amphetamine and cocaine, induce dramatic changes in dopamine signaling; large doses and prolonged usage can induce symptoms that resemble schizophrenia. Additionally, many antipsychotic drugs target dopamine receptors, especially D2 receptors.

Genetic hypertension

Dopamine receptor mutations can cause genetic hypertension in humans. This can occur in animal models and humans with defective dopamine receptor activity, particularly D1.