User:Jessica Gauldin/Sandbox1

This is a default text for your page Sandbox1595. Click above on edit this page to modify. Be careful with the < and > signs.

You may include any references to papers as in: the use of JSmol in Proteopedia ^[1] or to the article describing Jmol ^[2] to the rescue.

Structure

There are 5 classes of dopamine receptors (D1, D2, D3, D4, D5), all of which have similar structures since they are all part of a G-protein coupled receptor family. This means that the portion of the receptor spanning the inner part of the cell’s membrane is composed of seven membrane-spanning G-protein (guanine nucleotide binding) domains (Beaulieu). The D1 and D5 dopamine receptors are 80% homologous in their transmembrane domains, whereas the D3 and D4 dopamine receptors are 75 and 53% homologous, respectively, with the D2 receptor (Beaulieu). Meaning, all of the dopamine receptors have similar structures.

Proteins are a long chain of various amino acid sequences. Inside the binding pocket, the residues that are used to bind dopamine to the receptor are Asp-114, Ser-193, Ser-197, Phe-110, Met-117, Cys-118, Phe-164, Phe-189, Val-190, Trp-386, Phe-390, and Hist-394. Dopamine binds to the top of the receptor structure. The pocket formed by these residues is hydrophobic and the residues are consistent among human dopamine receptors (Kalani et al., 2004). In the dopamine receptor, both the N-terminus (amino end of the polypeptide chain) and the C-terminus (carboxyl-group end of the polypeptide chain) are located on the extracellular portions of the cell membrane. Furthermore, all dopamine receptors contain two cysteine amino acids on their extracellular portions whose disulfide bridge helps stabilize this protein (Missale et al., 1998).

Function

Dopamine is a neurotransmitter naturally found in the brain and acts specifically on dopamine receptors. It is classified as a catecholamine, meaning it is made from the amino acid, tyrosine. Dopamine is the precursor to both norepinephrine and epinephrine, which innervate the sympathetic nervous system, therefore its effects in the body are widespread (“Dopamine”). For instance, when these receptors are activated in the renal vasculature, this leads to renal blood vessel dilation, and an increase in glomerular filtration rate, renal blood flow, sodium excretion, and urine output.

Activation of dopamine receptors can either lead to an excitatory (D1, D5) or inhibitory (D2, D3, D4) response in the brain (Brown, 2015). When the excitatory receptors are activated, this activates adenylyl cyclase, a regulatory enzyme, which then increases the concentration of cAMP inside the cell (Dopamine Receptor). Activation of D2-like receptors generates an inhibitory response by preventing the formation of cAMP by inhibiting the adenylyl cyclase enzyme (Dopamine Receptor).

Ligands

Many psychostimulants including cocaine and methamphetamine produce a feeling of euphoria by the increase of dopamine in the neuronal synapse (Brown, 2015). In a normal cell, dopamine is taken back up into the presynaptic cell to recycle, but cocaine binds to the dopamine receptor on the presynaptic cell to block the reuptake by the dopamine receptor causing an increase in dopamine in the synapse ("How Does..."). In addition to preventing the reuptake of dopamine, methamphetamine increases the secretion of dopamine from the receptors by an unknown mechanism, which creates an even more intense feeling of euphoria (Kish, 2008). However the problem with these drugs, especially methamphetamine, is that habitual use of the drug can damage or even kill the neuron which would decrease the secretion of dopamine in the brain which is why methamphetamine abusers are predisposed to Parkinson’s disease (Granado et al., 2013). One of the reasons why methamphetamine is so dangerous is that not only does it affect dopamine, but it also promotes the release of other monoamine neurotransmitters including norepinephrine, epinephrine, and serotonin. Thereby over stimulating the sympathetic nervous system which can lead to high blood pressure and increased heart rate leading to cardiac arrest and death (Kish, 2008).

Disease and Relevance

In the United States, approximately 9.3% of people 12 years old and above struggle from some form of addiction (Treatment Statistics, 2011). Addiction is not only detrimental to the social and behavioral aspects of the person’s life, but it also affects their brain chemistry. Specifically, the use of a wide range of substances like alcohol and illicit drugs interact with dopamine receptors and induce an abnormally high level of Dopamine to flood the brain. Because Dopamine is the primary neurotransmitter in the human reward pathway, the brain begins to associate alcohol or other substance that cause the influx with the huge chemical reward. Initial use is usually caused by the desire to obtain their positive reaction but addiction occurs when the brain no longer functions optimally without the dopamine surge caused by the substance. Because addiction is not only caused by psychological desire but also biological desire it rapidly becomes a detrimental disease to those who suffer.

Malfunction of dopamine receptors also plays a role in a wide array of other neurological problems. There is a delicate balance that must be maintained for the human brain to function at the peak of it’s ability. For example, the psychological disorder schizophrenia is believed to be caused in part by a malfunction in multiple dopamine receptors that result in much higher than normal levels of dopamine, whereas the debilitating disease Parkinson’s is believed to caused in part by the dopamine receptors failing to release a sufficient amount of the neurotransmitter. In the case of schizophrenia it is currently accepted that a wide range of the positive symptoms, including hallucinations and delusions, originate because of an increased level of subcortical dopamine which in turn augments the D2 receptors and leads to even more release in areas of the brain like the nucleus accumbens. Some of the negative effects which include inability to form sentences and lack of outward motivation are hypothesized to be triggered by the reduced activation of D1 receptors (Brisch et al, 201). Parkinson’s, on the other hand, is caused in part by the destruction of dopamine receptors and thus the loss of a critical amount of the neurotransmitter. Dopamine is vital in relaying messages from the brain to the muscular system and disrupting this mechanisms produces tremors and a lack of balance which are common symptoms of the disease (Kim, 2002).