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NEUROTRANSMITTERS

 

 

 

NEURON

 

NEUROTRANSMITTERS WHOSE RECEPTORS ARE GPCRs

    While the messages which spread along a nerve cell (such as the human neuron pictured below) are electrical, the messages which pass from nerve cells to muscle cells, gland cells, or other nerve cells are chemical messages, transmitted by molecules called neurotransmitters and neuropeptides.  These molecules would be useless as messengers if the cells receiving these messages did not have receptors for neurotransmitters and neuropeptides.  G protein coupled receptors (GPCRs) are the receptors for most of these signals, and they mediate the signals of the nervous system which result in muscle contraction, hormone secretion, sensory awareness, emotions, memory, and personality. A large percentage of GPCRs are expressed in the brain and about 30% of pharmaceutical drugs target the GPCRs which interact with the signal peptides, lipids, neutrotransmitters, and nucleotides produced in the body (Vassilatis, 2003).

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

In addition to its roles in neural and muscle tissue, ACh is produced in other human tissues as well as the tissues of organisms without nervous systems, including sponges, fungi and plants.  ACh is even produced in both eubacteria and archaea (Yamada, 2005).

Cnidarians possess a GPCR for biogenic amines homologous to mammalian receptors for NE and E.  Cnidarians also seem to possess GPCRs which are homologous to dopamine and serotonin receptors (Bouchard, 2004).

 

DOPAMINE

     The neurotransmitter dopamine is involved in the perception and pursuit of pleasure.  It is involved in almost every type of addiction and dopamine treatment can decrease addiction.  Its release increases sex drive, is a factor in orgasm, and may cause premature ejaculation.   Higher than normal levels occur through cocaine use, sexual activity, periods of increased sexual receptivity, and in response to testosterone.  Dopamine has been used to treat Parkinsons disease and sex drive disorders and its level may be increased in schizophrenia.  Much of the feeling of euphoria associated with cocaine use results from the blocking of the reabsorption of dopamine.    Since dopamine receptors are expressed in both the brain and on white blood cells, there may be a link between personality and immune function (Czermak, 2004).   

 

     There are a number of dopamine receptors (DRD1 through DRD5).  Different alleles of these receptor genes affect a number of aspects of brain function ranging from neurological disorders to normal personality traits.

DRD1

     DRD1 receptors are expressed in the brain’s nucleus accumbens, caudate nucleus, and the olfactory tubercle and are also expressed in the ovary.  Dopamine is used in the kidney to regulate sodium and DRD1 mutations can affect sodium transport (OMIM).  The DRD1 gene is located in the region linked to bipolar disorder in some studies.  Bipolar disorder affects about 1% of the population and dopamine signaling is affected by medications which treat bipolar disorder (Ni, 2002).  Only one D1 dopamine receptor is known in jawless fish.  This number increased in the genome duplications early in vertebrate evolution.  Cartilaginous fish and amphibians possess three (Callier, 2003).

 

 

DRD2

     DRD2 alleles have been linked to schizophrenia, recurrent major depression, and adolescent emotional disorders.  Some studies have found associations between certain alleles and alcoholism and Parkinson-like disorders.  DRD2 receptors function in the coordination of movement and mutations may cause myoclonus dystonia.  Some mutations in mice cause abnormalities similar to those observed in Parkinsons disease.  In mice some mutations affect the response to morphine when used as a reward (but not other rewards such as food).  Some antipsychotic drugs act by blocking DRD2.

     The A1 allele of DRD2 is more common in those addicted to alcohol, cigarettes, opiates, and other substances and is associated with high novelty seeking and high harm avoidance (Berman, 2002).  The Ser311Cys allele of DRD2 is more common in those with persecution delusional disorder (Morimoto, 2002).  The density of DRD2 receptors in the striatum is correlated with the personality trait of detachment as are variants of the promoter which affect the density of receptors produced.  Novelty seeking is associated with density of DRD2 receptors in the right insular cortex as is increased blood flow to this region (Jonsson, 2003).

     Investigations into the contribution of DRD2 in schizophrenia have led to conflicting results, with some studies suggesting a link between DRD2 polymorphisms and the disorder.  A polymorphism in a gene located 3’ to DRD2, named “X-kinase” is linked to schizophrenia (Dubertret, 2004).  Different alleles of DRD2 seem to contribute to the difference in the effectiveness of medication which treats post-traumatic stress disorder (Lawford, 2003; Jonsson, 2003).

     The first documentation of interaction between different alleles of a gene and the environment was the 2000 report that children with minor alleles of DRD2 had greater extraversion when living in an alcoholic home while the opposite was true of children with major alleles of DRD2 (Ozkaragoz, 2000).

 

 

            DRD3

     DRD3 receptors are expressed in the limbic system and are involved in cognition, emotions, and hormone release.   Drugs which treat Parkinsons disease and psychosis may act on DRD3 receptors.  Increased expression of DRD3 receptors may be a factor in causing schizophrenia. Polymorphisms in DRD3 and DRD4 are linked to avoidant and obsessive personality traits (Joyce, 2003).  Reduction in the density of D3 receptors is involved in antipsychotic treatment (Seretti, 2000). The DRD3 gene is highly concentrated in the parts of the limbic system associated with reward.  It doesn’t seem to be involved in alcohol addiction (Gorwood, 2001).  DRD3 polymorphisms linked to the trait of persistence (Czermak, 2004).   The BalI polymorphism (which converts a serime to a glycine in condon 9 of the first exon of DRD3) is linked to schizophrenia (Petronis, 2000).  Studies have linked the 102T/C polymorphism of DRD3 to schizophrenia with the C allele being more frequently found in schizophrenics.  The original sequence seems to have been a C rather than a T given that this sequence is found in chimps and the CCG mutates to CTG much more frequently than the reverse change.  Since this change does not change the amino acid content of the protein, it is thought to affect methylation of the gene (Petronis, 2000).

 

 

NEURON

 

 

 

 

 

 

 

 

 

 

 

 

            DRD4

     DRD4 receptors are expressed in the limbic system and affect cognition, emotions, and anger.  This gene is one of the most variable human genes known with most of the variation occurring in exon 3.  Different alleles of DRD4 are associated with scores on personality tests related to novelty seeking (high scores with novelty seeking are correlated with impulsive and exploratory behaviors; low scores are correlated with being stoic, loyal, and frugal).   Increased expression of receptors may be a factor in schizophrenia and certain alleles may affect ADHD.  Some mutations in humans affect the functioning of the autonomic nervous system and some mutations in mice affect activity levels and sensitivity to drugs (OMIM).  Although DRD4 alleles were associated with variations in smoking prevalence in humans, this link was lost after controlling for novelty-seeking (Elovainio, 2004).

     Several drugs used to treat schizophrenia act on DRD4 and analysis of the brains of schizophrenics indicates that DRD4 expression is higher in schizophrenics (Xing, 2003).  A polymorphism upstream of the DRD4 region which may affect transcription rates is linked to schizophrenia.  This may explain the inconsistent findings of polymorphisms within the gene contributing to schizophrenia (Xing, 2003).

     Polymorphisms exist in the DRD4 gene of both humans and great apes and these include single nucleotide substitutions and variable tandem duplications of GC nucleotides (Shimada, 2004).

 

DRD5

     DRD5 receptors are expressed in the cortex, dentate gyrus, hippocampus, and substantia nigra.  There are a number of pseudogenes of DRD5, some of which are still transcribed in some tissues.  One allele of DRD5 is associated with a disorder which affects the eye muscles known as plepharospasm (Misbahuddin, 2002).  The human genome contains 2 DRD5 pseudogenes (Nguyen, 1991).

 

 

 

 

 

 

 

 

 

 

 

 

 

NEURONS

 

 

 

 

 

 

 

 

 

 

 

 

EPINEPHRINE

     Epinephrine is not only a neurotransmitter, but it also functions as a hormone when released from the adrenal glands during the fight or flight response.  Blood concentrations of neurepinephrine increase in ADHD. Some learning disabilities and some of the variations in NE receptors are correlated with ADHD, especially when accompanied with learning disabilities. Antidepressants such as Elavil prevent the reuptake of NE and serotonin form the synaptic cleft; prolonging their elevating effects.  Some antihypertensive drugs act in the PNS, blocking NE's stimulation of smooth muscle by binding to NE receptors. Amphetamines resemble NE and dopamine which are used at pleasure center (OMIM).

 

ADRA1A is expressed in the heart, liver, and prostate.

 

ADRA1B mutations in mice affect blood pressure.

ADRA2B and ADRA1B alleles seem to cause much of the individual variation in blood pressure.

 

ADRA1D

 

ADRA2A receptors are involved in the stimulation of the heart and are essential for the development of blood vessels in the placenta.  Mutations in mice affect heart contractability.  Cardiac muscle is depicted below.

 

 

CARDIAC

 

 

 

ADRA2B receptors are involved in basal metabolic rate and obesity.

 

ADRA2C mutations increase susceptibility to congestive heart failure.

 

ADRB1 polymorphisms are related to basal heart rate and susceptibility to congestive heart failure.

 

ADRB2 alleles can increase susceptibility to nocturnal asthma and susceptibility to obesity.

 

ADRB3 is primarily expressed in adipose and is involved in lipolysis and thermogenesis.  Certain alleles increase susceptibility to obesity and non-insulin dependent diabetes.  One particular allele (W64R) is common in Pima Indians, who are often used in studies on lipid metabolism.

 

 

 

 

 

 

 

 

 

 

 

NEURON

 

 

 

GABA (gamma amino butyric acid)

     GABA is the major inhibitory neurotransmitter of the vertebrate brain.  More than a dozen genes code for the subunits which can be combined to form the receptor protein.  GABA receptors interact with barbituates, ethanol, and benzodiapezine.  There are several classes of subunits (alpha, beta, gamma) whose members share 70-80% homology in each class and 30-50% homology is observed between these classes.  One cluster on chromosome 15 possesses the GABA receptor genes B3—A5—G3 and duplications of this cluster seem to have given rise to the cluster on 5q34 containing the genes B2—A6—A1—G2 and the cluster on 4p12 containing the genes B1—A4—A2—G1. 2.   Tranquilizers such as valium and librium bind to GABA receptors, enhancing its inhibitory effect (OMIM).  GABA receptor polymorphisms have been linked to anxiety and the effects of alcoholism (Reif, 2003).

 

GABRA1 mutations cause epilepsy and juvenile myoclonia.

 

GABRA2 is expressed in the limbic system and it mediates the effects of anti-anxiety drugs.

 

GABRA3 is expressed in the reticular activating system.

 

GABRA4

 

GABRA5 is located in the region which is deleted in the Prader-Willi and Angelman syndromes and may be responsible for some of the effects of these disorders.  One study correlated a CA repeat in this gene to bipolar disorder. Variants of the GABA type A receptor α5 have been linked to susceptibility to bipolar disorder (Otani, 2005).

 

GABRA6 is expressed in the cerebellum (pictured below).

 

 

 

 

 

 

 

 

 

 

 

NEURON

 

 

 

GABRB1

 

GABRB2

 

GABRB3 mutations have been linked to insomnia and autism.

 

GABRD

 

GABRE is expressed in the brain, heart, and placenta and alternate splicing can produce tissue specific forms.  Mutations may be involved in retardation and early onset Parkinsons disease.

 

GABRG1

 

GABRG2 and GABRG1 mediate the effects of the drug benzodiapezine.  One of the splicing variants of GABRG2 interacts with ethanol.  Mutations can cause epilepsy and febrile seizures.

 

GABRG3

 

GABRP is expressed in several tissues including the uterus and mediate the effects of the drug pregnanolone.

 

GABRQ is expressed in many regions of the brain.

 

GABR Rho1

 

GABR Rho2 is expressed in the retina.

 

GABA B Receptor 1 GABBR1 is expressed throughout the brain, small intestine, and uterus.  Mutations in mice result in seizures, memory problems, and EEG abnormalities.

 

The glycine receptor is homologous to the GABA receptor. Amino acid changes at residues 159 and 161 convert the wild type receptor which responds to glycine into a mutant channel which responds to GABA (Schmieden, 1993).

 

 

NEURON

 

 

 

GLUTAMATE

     Glutamate is the major excitory neurotransmitter in the mammalian brain.  There are two classes of glutamate receptor, ionotropic and metabotropic.  The ionotropic receptors are divided into the NMDA receptors and the non-NMDA receptors (such as GRIA and GRIK).  The metabotropic receptors can be grouped on the basis of structure and function (GRM1 and 5 are grouped together, as are GRM 2 and 3, and GRM 4 and 6).

     Glutamate is a neurotransmitter in the central and peripheral nervous systems.  The glutamate receptors expressed in insect muscle are the functional equivalents to nicotinic acetylcholine receptors in vertebrates (Schuster, 1991).

 

1A) IONOTROPIC, NMDA

NMDA receptors are involved in associative memory.

 

GRIN1 is the major subunit in all NMDA receptors; one or more of the following GRIN receptors are also incorporated into the protein.  NMDA receptors located at synapses increase the activity of CREB and BDNF genes (involved in learning), and are antiapoptotic (prevent cell death).  NMDA receptors which are not located at synapses are activated in hypoxia, inducing membrane potential changes in the mitochondria and apoptosis (programmed cell death).  A decrease in NMDA receptors may be a factor in schizophrenia.

 

GRIN2A mutations in mice interfere with memory.

 

GRIN2B mutations cause death in homozygous mice.  Transgene mice which expressed increased amounts of GRIN2B performed better at memory tasks than wild type mice.

 

GRIN2C mutations in mice caused motor abnormalities.

 

GRIN2D mutations in mice result in some abnormal behaviors.

 

GRIN3A receptors are widely expressed.

 

GRIN3B receptors are expressed on motor neurons.

 

GRINL1A

 

1B) Non-NMDA IONOTROPIC RECEPTORS

 

GRIA1 mutations in mice interfere with learning.

 

GRIA2 is essential for normal brain function and is also involved in the perceived reward from cocaine.

 

GRIA3 mutations cause Rasmussen encephalitis whose effects include inflammation, epilepsy, and dementia.

 

GRIA4

 

GRIK1 receptors are expressed in the ventral horn of the spinal chord.  Mutations can cause juvenile absence epilepsy.

 

GRIK2 polymorphisms affected the age of onset of Huntingdon disease.

 

GRIK3

 

GRID2 mutations in mice cause the lurcher” phenotype which includes ataxia, the death of cerebellar Purkinje cells (pictured below), and eventually death of the mice

 

 

NEURONS

 

 

 

2)       METABOTROPIC RECEPTORS

GRM1 mutations cause learning and motor abnormalities.

 

GRM2 mutations result in abnormal responses from the hippocampus.

 

GRM3

 

GRM4 is expressed most highly in the cerebellum.  Mutations affect learning.

 

GRM5

 

GRM6 receptors are expressed in retinal cells where they function in synaptic transmission.

 

GRM7

 

GRM8 is expressed in the retina and brain.

Among GPCRs, the MRG family of receptors detect pain stimuli in sensory neurons (such as RFamide neuropeptides).  The gene MRGX2 has undergone positive selection in the human lineage, suggesting an adaptation of the sensory system (Yang, 2005).

 

 

 

 

 

 

 

 

 

 

 

OPIATES

     Endorphins, enkalphins, and dynorphin are our brain’s own opiates that reduce our sensitivity to pain (may be felt during exercise [“runner’s high”] and the fight or flight response).  Enkalphins are secreted during labor.   Opioid receptors mediate the effects of endogenous opiates (enkalphins, endorphins, dynorphin) as well as those of morphine, heroin, and methadone.  

     Mammals possess 3 opioid receptors (plus an opioid-like receptor which binds to nociceptin).  The receptors are classified as mu, kappa, and delta.  Six opioid receptor-like proteins are known from a teleost fish which are homologous to the m-opioid receptors (Darlison, 1997).  No opiod receptors are as yet known from invertebrates but opioid peptides are known to be secreted some invertebrates (such as mollusks) (Darlison, 1997).

 

OPRM1 is the major receptor site for the binding of heroin, morphine, and methadone.  There are ethnic differences is the distribution of OPRM1 alleles and some alleles increase vulnerability to these drugs.  One mutant receptor binds beta-endorphin three times the degree observed in wild type receptors.  Mutations can cause epilepsy.

 

OPRK1 forms a heterodimer with OPRM1.

 

OPRD1

 

 

 

 

 

 

 

 

 

 

 

 

 

NEURON

 

 

 

 

 

 

 

 

 

 

 

 

SEROTONIN

     The neurotransmitter serotonin inhibits sex drive and orgasm; promotes contentment, causes cravings for sweets and has been used to treat depression, obsessive-compulsive disorder, panic, anxiety, PMS.   Prozac increases serotonin levels and dieting decreases them. Receptors for serotonin are involved in the regulation of sleep, appetite, thermoregulation, pain, and sexual drives.  Abnormalities in serotonin pathways can result in depression, migraine, and obsessive-compulsive behavior.  The different subgroups of receptors are distinguished by the number in their name: HTR1 (A,B,D,E,F), HTR2, HTR3, etc.  The genes HTR1A, 1B, 1D, and 1E lack introns and are more similar to the adrenergic receptors (which are also G-protein coupled receptors) than they are to other serotonin receptors.  Some receptors mediate responses through adenylate cyclase; others through phospholipase. LSD binds to serotonin receptors, blocking the inhibition of some pathways.  Some sensory information is no longer filtered resulting in a sensory overload (OMIM). 

     Serotonin receptors are expressed in the CNS, PNS, and other tissues and are involved in depression, anxiety, schizophrenia, obsessive-compulsive disorders, panic disorders, migraine, hypertension, eating disorders, and irritable bowel syndrome (Hoyer, 2002).  Studies have suggested that abnormalities in the serotonin system may be a factor in aggression and pedophilia (Maes, 2001).

     There are at least 14 serotonin receptors (although 5-HT3 is a ligand-gated ion channel rather than a GPCR like the others).   Serotonin also affects the 5-HT transporter which a number of drugs are known to act on this transporter  (Hoyer, 2002).  

 

HTR1A

Mutations in 5HT1A receptors in mice increased levels of anxiety (Reif, 2003).  

 

HTR1B is most highly expressed in the striatum.   Mutations in 5HT1B receptors in mice increase aggression, exploratory behavior, and the susceptibility to addition to cocaine and alcohol.  Variants of the 5HT1B receptor have been linked to increased frequency of alcoholism in two human populations (Reif, 2003).

 

HTR1C variants can cause audiogenic seizures and visual hallucinations.  

 

HTR1D is most highly expressed in the caudate nucleus.

 

HTR1E

 

HTR1F is expressed in the cortex, hippocampus, and striatum.

 

HTR2A receptors are imprinted and only the maternal allele is expressed.  One variant is associated with schizophrenia and with auditory and visual hallucinations.  A G/A polymorphism in the promoter of serotonin 2A receptor gene (position -1438) has been correlated with seasonal affective disorder, anorexia, and obsessive compulsive disorder (although other studies have produced negative results).  Studies of prison inmates have also shown differences in the frequency of alleles at this site compared to control populations (Beggard, 2003).

 

HTR2B is expressed in the heart and blood vessels and variants can cause hypertension.

 

 

 

 

 

 

 

 

 

 

 

 

VESSEL

 

 

 

 

 

 

 

 

 

 

 

 

HTR2C mutations in mice cause seizures (including audiogenic seizures) and weight gain.  Variants in 5HT2c receptors and DRD4 receptors may interact to determine reward dependence and persistence (Reif, 2003).

 

HTR3A is located on the region of chromosome 11 which some have linked to schizophrenia and bipolar disorder.

 

HTR3B is expressed in the brain, monocytes, intestine, uterus, ovary, and placenta.

 

HTR4 is expressed in the heart.  In some mammals (such as humans, monkeys, and pigs), the atria respond to serotonin while in other mammals (such as rodents) this response does not occur.

 

Antimigraine drugs interact with 5-HT1D/1B. (Hoyer, 2002).    

 

HTR6

 

HTR7

 

 

 

 

 

 

 

 

 

 

 

TRACE AMINES

Trace amines are produced by all animals and many (perhaps all) eukaryotes and prokaryotes. In mammals, these trace amines include β-phenylethylamine (PEA), tyramine (TYR), octopamine (OCT), synephrine (SYN), and tryptamine (TRYP) . Invertebrate trace amines include OCT and TYR. Receptors for trace amines form a family of GPCRs which has expanded through duplications (Grandy, 2007). Trace amines include β-phenylethylamine (PEA), tyramine, octopamine (OCT), synephrine, and tryptamine (TRYP). Trace amines have been identified in every animal (vertebrate and invertebrate) studied to date, they are typical of unicellular organisms (eukaryotic and prokaryotic) as well. Humans can encounter them in sources as diverse as chocolate, cheese, beer, ergot-infested rye, and rotting meat (Grandy, 2007)

Although trace amine receptors are found in both vertebrates and invertebrates, the receptors in these two groups are not very similar, indicating that the evolution of trace amine receptors has occurred twice within animals.  One group of GPCRs in the rhodopsin family are activated by trace amines. There are 15 receptors in this family known from both the human and mouse genomes such as TA1 which binds tyramine and β-PEA and TA2 which binds β-PEA. In addition, the pseduogenes GPR58, GPR57, the 5-HT4 pseudogene, and the orphan receptor PNR are related to this group. The mammalian members of this gene family are related to the invertebrate receptors for tyramine, octopamine and 5-HT (Borowsky, 2001).In humans, it is possible that trace amines are involved in some mood disorders. There has been significant expansions in the number of trace amine receptors in zebrafish (as compared to other fish) and in rodents (Gloriam, 2005).   

    .  In vertebrates, the effects of the biogenic amines norepinephrine, dopamine, and serotonin are mediated through G-protein coupled receptors.  Mammalian nervous systems possess GPCRs which interact with these trace amines as well.  While invertebrate nervous systems use biogenic amines such as tyramine, b-phenylethylamine, tryptamine, and octopamine as neurotransmitters, the role of these trace amines in vertebrate nervous systems is not yet clear.  The receptor TA1 interacts with the trace amine tyramine and b-phenylethlamine and TA2 interacts with b-phenylethylamine.  These two receptors belong to a family of GPCRs (TA1 through TA15) whose function is not well understood (Borowsky, 2001).  There is a trace amine receptor TA3 expressed in the pituitary gland and skeletal muscle.  Although a null allele of these gene is fairly common in humans (with a frequency of about 20%), no effects are known (Vanti, 2003).

 

TA1

TA2

TA3

TA4

TA5

TA6

TA7

TA8

TA9

TA10

TA11

TA12

TA13

TA14

TA15

 

In mammals, the trace amines tryamine, tryptamine, β-phenylethylamine, and octopamine belong to a group of monoamines which are known from invertebrates, plants, and even bacteria (Gloriam, 2005).

 

In invertebrates, octopamine may function as the equivalent of epinephrine in vertebrates.

 

 

NEUROPEPTIDES WHOSE RECEPTORS ARE GPCRs

 

 

 

 

 

 

 

 

 

 

 

 

NEURON

 

 

 

 

 

 

 

 

 

 

 

 

     There are more than 60 neuropeptides in the mammalian brain; most of them act through GPCRs.  Neuropeptides serve as neuromodulators in vertebrate and invertebrate nervous systems and can function as neurotransmitters in invertebrates.  In nematodes, about 130 putative receptors for neuropeptides have been identified.  In mammals, neuropeptides function in a variety of neural pathways, including those involving feeding and sleep (Nathoo, 2001). Flatworms (platyhelmiths) possess GPCR neuropeptide receptors (Omar, 2007).

 

Bombesin is expressed in the CNS and GI tract.  It affects muscle contraction, exocrine and endocrine gland function, metabolism, and behavior.

 

BRS3 mutations in mice result in abnormal metabolism and hypertension.

 

GRPR (gastric releasing polypeptide receptor) is produced in the brain and binds to bombesin.  It is needed for growth and may be involved in some carcinomas.

 

Galanin is expressed in the diencephalon and in other brain regions and in the gastrointestinal tract.  It effects neurotransmitter release, pain, appetite, growth hormone secretion, heartbeat, gastric motility, and sexual activity.  GPRs 40 through 43 are located in a cluster on chromosome 19q13.

GAL1

 

GAL2

 

GAL3

 

GPR40

 

GPR41

 

GPR42

 

GPR43

 

Neuromedin affects blood flow and ion transport and is involved in feeding control pathways.  

NMBR promotes growth in the lung and lining of the gastrointestinal tract.

 

NMU2R stimulates smooth muscle, affects blood flow and blood pressure, and maybe involved in feeding.

 

GPR66 affects blood flow and blood pressure, and maybe involved in feeding.

 

Neuropeptide Y

Neuropeptide Y is the most abundant neuropeptide in mammals.  It is involved in the regulation of feeding, endocrine function, and vasoconstriction.  

 

NPY1R is expressed in the brain, spleen, small intestine, kidney, aorta, testis, and placenta.  It is required for the release of substance P (involved in the sensation of pain) and the initiation of neurogenic inflammation.

 

NPY2R is expressed in the central nervous system.

 

NPY5R is expressed in the hypothalamus and is involved in feeding regulation.

 

NPY6R is expressed in skeletal and cardiac muscle in primates (this may represent a novel adaptation found in primates).

 

The receptor for prolactin-releasing hormone (PRLHR) are related to neuropeptide Y receptors (in the rhodopsin group of GPCRs) and seem to have evolved from a redundant duplicate of a NPY receptor.  PRLH is secreted from the hypothalamus and several other brain regions and affects food intake and prolactin secretion (Lagerstrom, 2005).

 

Neuropeptide FF

            NPFF1

 

            NPFF2

 

Neurotensin modulates the effects of dopamine.

NTSR1

 

NTSR2

 

Nociceptin is involved in the perception of pain.

OPRL1, Opiate Receptor-Like 1

    This receptor binds the neuropeptide nociceptin/orphanin.  Neutrophils and monocytes also express this receptor.

 

Orexin (hypocretin) A and B are involved in food consumption and some receptor variants can cause symptoms similar to narcolepsy. Two neuropeptides, the hypocretins, are homologous to the peptide hormone of the gastrointestinal tract, secretin.   They are members of the incretin hormone family, mediate their actions through GPCRs, and are expressed in the hypothalamus.  At least one may function as a true neurotransmitter (de Lecea, 1998).

 

HCRTR1

 

HCRTR2

 

Somatostatin is a neuropeptide that affects neuronal electrical activity and inhibits GH secretion.  

SSTR1

 

SSTR2 is involved in neuroblastoma.

 

SSTR3 is coupled to adenylate cyclase unlike SSTR1 and 2.

 

SSTR4 is expressed in the brain and lung.

 

SSTR5 can interact with dopamine receptors.

 

Cannabinoid receptors respond to endogenous neuropeptides whose effects are anti-inflammatory, immunosuppressive, anticonvulsive, and can relieve intraocular pressure in glaucoma.  They also affect memory.  Both of the receptors are involved in the extinction of aversive memories (OMIM). Homologs of cannabinoid receptors are known throughout eukaryotes (McPartland, 2006). CB1 and CB2 are the GPCRs which respond to marijuana and endocannibinoids (those produced by the body). CB1 is most highly expressed in the hippocampus and cerebellum but is also expressed outside the brain in the spleen, testis, and white blood cells.  CB2 is primarily expressed in white blood cells.  Both are expressed in the placenta (Onaivi, 2002). The proteins which function in the human endocannabinoid system arose at different points in evolution—some are specific to eukaryotes, bilaterans, chordates, vertebrates, and mammals. Some organisms make use of cannibinoids but lack cannibinoid receptors (McPartland, 2005).

     Endocannibinoids are modified eicosinoid-like fatty acids. Given the production of encannibinoids in the fetal brain, these substances may function in development.  Endocannibinoids also seem to function in immunity, cell growth, learning, and inflammatory reactions.  They may be produced from cell membrane lipids after receptor-ligand interaction and function as a retrograde signal (Onaivi, 2002).  The brain of a developing pig is depicted below.

 

 

 

 

 

 

 

 

 

 

 

 

BRAIN

 

 

 

     Endocannibinoids can also activate the vanilloid subtype 1 capsaicin receptor (VR1) which can be activated by capsaician from plants (such as hot peppers) and function in pain perception (Onaivi, 2002).  Activation of CB1 and CB2 can reduce the responses of T and B cells in immune responses (Onaivi, 2002).

     Cannibinoid receptors are widespread in invertebrates (nematodes, planarians, leeches, insects, mollusks) and vertebrates (known in mammals, birds, and frogs).  Cyanobacteria and protists are able respond to endocannibinoids as well. Marijuana use can alter memory and learning pathways (Onaivi, 2002).

CB1

 

CB2

 

The expression of the MRG family of GPCRs is limited to a group of pain receptors which bind RFamide neuropeptides (Yang, 2005)

PERSONALITY

     Current evidence suggests that personality traits are not determined by single genes but rather by the additive functions of a number of genes, many of which are polymorphic in human populations (and which will likely be shown to interact with the environment).  Some personality traits seem to be more affected by genes and others more affected by the environment.  Some personality disorders may reflect the extreme expression of normal components of personality (Reif, 2003).  It is thought that any single gene does not typically cause more than 1-2% the observed variance of a personality trait (Czermak, 2004).  

 

SEROTONIN

     Although variations in serotonin receptors can affect behavior, there are other proteins involved in the use of serotonin as a neurotransmitter whose variations are also significant. Low serotonin levels or turnover have been linked to suicide, impulsive behavior, aggression, and low social status (the latter observed in primates) (Reif, 2003).  Harm avoidance is determined by serotonin (Berman, 2002).   

 

     The enzyme tryptophan hydroxylase, located only in neurons of the raphe nucleus, catalyzes the most important of the two reactions which convert tryptophan to 5HT (serotonin). Variations in tryptophan hydroxylase (TPH) have been linked to aggression and suicidal behavior (Reif, 2003).

     Once serotonin is released as a neurotransmitter, it can be reabsorbed for subsequent reuse by the neuron using a 5HT transporter (5HTT) or degraded to 5HIAA by monoamine oxidase A (MAO-A) (Reif, 2003).   The 5HTT gene is regulated by an upstream polymorphic repetitive element (known only in humans and simian primates).  Variants in this transporter repetitive element (5HTTLPR) have been linked to neuroticism, agreeableness, and anxiety.  The concentration of 5HIAA (the breakdown product of serotonin) in cerebrospinal fluid has been shown to vary in monkeys depending on whether young rhesus monkeys were raised by their mothers or their peers, but only in monkeys the s allele of the serotonin reuptake transporter repetitive element.  These alleles also influence the age at which rhesus monkeys leave their group (Reif, 2003).

 

DOPAMINE

     Although variations in dopamine receptors can affect behavior, there are other proteins involved in the use of dopamine as a neurotransmitter whose variations are also significant.

 

     Dopamine converted from tyrosine by the enzyme tyrosine hydroxylase (TH) and aromatic amino acid decarboxylase (Reif, 2003).  Variants in the TH gene have been linked to neuroticism, angry hostility, vulnerability, suicidal behavior, and alcoholism (Reif, 2003).  Tyrosine hydroxylase controls the synthesis of E and NE is a factor in some mood disorders (Seretti, 2000).  

 

Catecol-O-methyltransferase (COMT) is an enzyme which breaks down dopamine, epinephrine, and neurepinephrine.  Deletions in the region of this gene are associated with psychosis (Collier, 2003).

 

     Although both serotonin and dopamine are perceived by multiple receptors, both are reabsorbed into neurons by a single reuptake transporter.  There is some evidence that variations in the dopamine transporter (DAT) may influence personality such as avoidant behavior (Reif, 2003).

     Monoamines are deaminated by MAO-A and the catecholamines are methylated by COMT. There are two genes for monoamine oxidase, MAO-A and MAO-B.  Deletions of MAO-A in humans result in mental retardation, autistic behavior, and other abnormalities (Reif, 2003).  Mutations in MAO-A and 5TTT affect the organization of the cerebral cortex in mice (Reif, 2003).

     The absence of MAO-A expression in mice results in increased levels of some neurotransmitters (dopamine, serotonin, and NE), higher aggression, and inappropriate sexual activity in males.  In humans, a mutation in MAO-A causes Brunner syndrome in which males suffer from mild retardation and display a variety of aggressive and hypersexual behaviors (in addition to other behaviors ranging from arson to suicidal behavior).  This is the only example known which fulfills the OGOD (one gene, one disease) model for behavioral disorders.  Variations in the promoter region are known to affect panic and depression in females and aggression in males (Reif, 2003).

      COMT variations have been shown to affect aggression in males and females.  Gene interaction (epistasis) has been observed between DRD4 and polymorphisms of the 5HTTLPR and COMT (Reif, 2003).

 

GABA

GABA levels are inversely associated with aggression and the interaction of GABAA receptors with alcohol, bezodiazepines, and barbiturates, can increase aggressive behavior.  The brain actually synthesizes steroid hormones which can interact with GABAA receptors (Miezek, 2003).

 

     The neurotransmitter norepinephrine is synthesized from dopamine by dopamine β-hydroxylase (DBH).  Variant forms of this enzyme may affect irritability (Reif, 2003).

 

     Neuregulin 1 affects cellular migration in the cerebrum and cerebellum, the growth of glial cells, and the expression of neurotransmitter receptors.  

 

     Of course, there are many factors other than genetics which can affect personality and the biochemistry of the brain.  Schizophrenia may affect up to 1% of the world’s population.  Non-genetic contributions may arise from problems during pregnancy and delivery, urban environments, childhood viral infections, marijuana use, and the age of the father (Collier, 2003).  Season of birth has been implicated in variations in schizophrenia, bipolar disorder, circadian rhythms, novelty seeking, neurotransmitter metabolism, and suicidal tendency (Chotai, 2003).

 

 

 

 

 

 

The mammalian GABA transporter is homologous to a fly protein and has comparable intron positions (Liu, 1992).