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G PROTEIN COUPLED RECEPTORS

SIGNAL TRANSDUCTION

     The cells of the human body (such as human neurons pictured above) depend on receiving signals—they need to know when to store glucose, when to divide, when muscles should contract, when neurons should fire, etc.  The molecules that send these signals typically do not enter the cell.  How can a hormone, or a neurotransmitter, or a growth factor stimulate cells that it does not enter?  Signaling molecules affect their target cells through a second messenger system in which activated intracellular second messenger molecules mediate the changes which occur inside a cell.  Molecules of adenylate cyclase create the second messenger cAMP (cyclic AMP which is produced by removing two phosphate groups from ATP).  Adenylate cyclase is activated by stimulated G proteins.  Normally, G proteins bind GDP and are unable to bind adenylate cyclase; when G proteins are themselves activated, they bind GTP and are able to activate adenylate cyclase.  G proteins are activated by G-protein coupled receptors which have bound their specific ligand, the signal which initiated this cascade.

     In the following illustration, the G-protein coupled receptor has not bound its ligand; and the G protein has not been activated.  As a result, adenylate cyclase has not been activated and the second messenger cAMP is not being made to initiate changes in the cell.

NEURON
CHANNEL
In the following illustration, the G-protein coupled receptor has bound its ligand, which activates the G protein, which stimulates adenylate cyclase to produce cAMP from ATP.  The cAMP then initiates changes in the cell.
CHANNEL 2
G-protein coupled receptors (GPCRs) belong to a giant gene superfamily (Pin, 2004).  The cells of the body react to different stimuli because different cells express different GPCRs.  In the following three illustrations, three different GPCRs in three different cells bind three different ligands to activate these cells.
GPCR
GPCR
GPCR

    GPCRs mediate many of their effects through the activation of the four groups of MAPK cascades: extracellular signal-related kinase (ERK), Jun N-terminal kinase (JNK), p38MAPK, and big MAPK (BMK).  Gonadotropin-releasing hormone receptors activate all four MAPK pathways (Naor, 2000).

Some GPCRs can activate intracellular proteins without using G proteins as intermediates (Pin, 2003).

 

G PROTEIN COUPLED RECEPTORS

    The superfamily of G protein coupled receptors share a set of 7 hydrophobic transmembrane regions connected by hydrophilic sections which form either intracellular or extracellular loops.  Modifications to the extracellular loops can alter the signaling molecules that the receptor can interact with.  The receptor for TSH only differs from the receptor for LH by 2 insertions in the extracellular domains (one insertion codes for 8 amino acids, the other for 50).  The modification of one amino acid in a GPCR, such as the asn residue in the seventh transmembrane domain of bioamine receptors, can be responsible for pharmacological differences in similar receptors (Vernier, ).  Not only has variation of the extracellular regions resulted in receptors which can react to a diversity of signaling molecules produced inside a multicellular organism (most polypeptide hormones, neurotransmitters, growth factors, extracellular calcium etc.), but also with a diversity of stimuli from the environment.  G protein coupled receptors include the receptors that humans use to detect taste, smell, and even light.  The cells which perceive taste are depicted below.

TASTE BUD

Some GPCRs even include co-receptors for the HIV virus and some alleles of these genes reduce susceptibility to infection.

     Mutations of GPCRs can cause a variety of human disorders including cancer, diabetes insipidus, SCTH deficiency, GH deficiency, pseudohermaphroditism, precocious puberty, chondrodysplasia, and thyroid/parathyroid disorders (Spiegel, 1996).  Some mutations in these receptors can prevent the cells of the body from reacting to the appropriate signals (loss of function mutations) while others produce receptors which are constitutively activated, regardless of whether the appropriate ligand is present (gain of function mutations).  The human disorders which can be caused by constitutively active GPCRs include familial hyperparathyroidism, precocious puberty, Jansen metaphyseal chondroplasia, congenital night blindness, retinitis pigmentosa, and familial non-autoimmune hyperthyroidism (Aranitakis, 1998).  GPCRs are often involved in the treatment of disease and are the targets of 30-60% of modern drugs (Takeda, 2002).

     In the following illustrations it is significant that the GPCRs which respond to a neurotransmitter in the brain, to olfactory stimuli in the nose, and to light in the eye all share the same basic structure.

 

b adrenergic receptor

RECEPTOR 1
RECEPTOR 2
OLFACTORY RECEPTOR
OLFACTORY

 

Common basic structure of 4 human visual opsins

OPSIN
  This superfamily of genes represents the largest gene family in the human genome.  The diversity of receptors has resulted from the duplication of smaller sets of ancestral receptor genes which were subsequently modified (Fredriksson, 2003a; Josefsson, 1999).  This gene family is an ancient family which transduces signals in organisms as primitive as bacteria.  For example, the light-detecting bacteriorhodopsin is homologous to GPCRs of higher organisms although exon shuffling has changed the order of the transmembrane regions (Pardo, 1992; Bartus, 2003).  Proteorhodopsin is a bacterial proton pump powered by light energy which generates ATP (Beja, 2001).  Archea and fungi also express opsins (Bieske, 1999).  The family of archael rhodpodsins has diversified to produce H+ pumps, Cl- pumps, sensory rhodopsin and phoborhodopsin from duplications in the ancestors of halophilic archaea.  Although archaeal rhodopsins are composed of 7 transmembrane alpha helices as in eukaryotic GPCRs, their sequences lack significant homology (which is not unexpected given the estimated two billion years since the divergence of the two lineages) (Ihara, 1999).  Archaea are depicted below.
ARCHEBACTERIA

      GPCRs compose the largest gene family in eukaryotes (Bartus, 2003).  Plants lack a variety of GPCRs and also lack some of the GPCR regulatory mechanisms known in animals such as GRKs, arrestins, and RGS proteins (Andreeva, 2001).  Unicellular yeast respond to mating pheromones through G-protein coupled receptors, reminiscent of homone-receptor interactions of animals (Blumer, 1998; Poggeler, 2001).  Gene duplication had produced many of the subfamilies of the G proteins and protein tyrosine kinases before the lineages leading to modern sponges separated from those leading to higher animals (Suga, 1999).  GPCRs represent more than 5% of the genome of the nematode C.elegans (with more than 1000 genes) and 1% of the genome of Drosophila (with 160 genes; (Rouquier, 2000; Zozulya, 2001; Takeda, 2002; Halpern, 2003; Chyb, 2004).

   GPCRs can be divided several large families within the superfamily: Family A containing rhodopsin related proteins, family B with proteins related to glucagon, PTH, and calcitonin receptors; family C with metabotropic glutamate receptors (including vomeronasal receptors type 2), family D consisting of pheromone receptors in yeast; family F known from slime molds; and additional proposed families (such as vomernasal receptors type 1, Frizzled homologs, and receptors known from plants).    Families C and D seem to be more related to each other than they are to the other groups.  Plants are known to possess members of families A, B, and F (Josefsson, 1999) although GPCRs did not expand in plants the way they did in animals (Pin, 2003). The rhodopsin group of GPCRs is the largest group and includes proteins which bind a variety of amines, purines, and peptides (Fredriksson, 2003a).  An additional family which bind cAMP is not yet known in  humans (Bockaert, 1999).

    One family of GPCR proteins (family C) includes glutamate receptors, GABA receptors, sweet taste receptors, amino acid taste receptors, and some pheromone receptors.  This group is an old group and is known in slime molds and sponges (Pin, 2003).

     There are groups of G proteins which share regions other to the transmembrane regions such as the hormone binding region shared by calcitonin, glucagons, GHRH, VIP, PACAP, parathormone, and others.  At least 30 human GPCRs within the secretin group share a very long N terminal region (Fredriksson, 2003a).  GPR 124 and 125 share an N-terminal region, a leucine rich repeat, an immunoglobulin domain, and a hormone biding domain (Fredriksson, 2003a). 

     Higher eukaryotes share the same components of G-protein signaling pathways including ligands, GPCRs, effector pathways, heterotrimeric G proteins, and regulator proteins (although the latter group has not yet been demonstrated in plants).  The basic pattern of this form of signal transduction had evolved by the separation of eukaryotic lineages (Sierra, 2002).  Sponges have a metatropic glutamate/GABA-like receptor of the GPCRs (Muller, 2001).

     More than 1% of the vertebrate genome is composed of GPCRs, apparently with more than 1000 odorant and pheromone receptors.  The basic organization of G proteins has been modified in some cases by differential splicing, RNA editing, and phosphorylation (Bockaert, 1999).

     Many of the following GPCRs are compared to others which are known to be receptors for hormones, neurotransmitters, neuropeptides, etc.  Many of the following GPCRs are “orphan receptors” whose ligands are as yet unknown.

    Not only do GPCRs interact with G proteins, they can be inhibited by arrestins (which cause desensitization and mark receptors for internalization).  Some GPCRs interact with proteins other than G proteins, such as β2 adrenergic receptors (Bockaert, 1999).

 

GPR1 is expressed in the hippocampus and is similar to opioid receptors.

 

GPR2 is expressed in melanocytes, fibroblasts, endothelial cells, and Langerhans cells and is similar to interleukin receptors.

 

GPR3 is expressed in the CNS, lung, and kidney.

 

GPR4 is expressed in various tissues.

 

GPR5

 

GPR6 is expressed in the putamen and other regions of the brain.

 

GPR7 is similar to opioid receptors and is primarily expressed in the cerebellum and the frontal cortex (cerebellum pictured below).

CEREBELLUM

 

GPR8 is similar to opioid receptors and is expressed in the frontal cortex.

 

GPR10 is similar to some neurotransmitter receptors.

 

GPR12 is primarily expressed in the brain.

 

GPR14 is the receptor for urotensin which affects heart contraction and vasoconstriction.

 

GPR15 is expressed in all tissues tested; its expression is highest in the placenta and skeletal muscle (placenta pictured below).

PLACENTA

GPR17 is expressed in the brain.

 

GPR18 is expressed in the testis, spleen, and immune tissues.  Cells of the spleen are depicted below.

THYMUS

GPR19 is expressed in the thalamus and basal nuclei.  In mice, its expression distribution is similar to that of dopamine D2 receptors.

 

GPR20 is expressed in the brain and liver. 

 

GPR21

 

GPR22

 

GPR23

 

GPR24 is the somatostatin receptor.  Mutations in mice decrease the formation of adipose.

 

GPR25

 

GPR26 is expressed throughout the brain.

 

GPR27 is most similar to those GPCRs which detect amino acids (such as norepinephrine and serotonin) and is expressed in the brain, heart, and gonads.

 

GPR30 is overexpressed in some breast carcinomas.  It is expressed in all tissues and is highly expressed in the placenta.

 

GPR31 is expressed in the placenta.

 

GPR32 is similar to the receptors for chemoattractants.

 

GPR33 is a pseudogene related to GPR32.

 

GPR34 is expressed in several brain regions.

 

GPR35 is expressed in all tissues examined and is most highly expressed in the lung, small intestine, colon, and stomach.

 

GPR37 is similar to endothelin receptors.  In interacts with parkin, a protein involved in some forms of Parkinsons disease.

 

GPR38 is the motilin receptor; motilin is produced in the cerebellum and gastrointestinal tract.

GPR39 is similar to GH secretagogue receptors.

 

GPR44 is similar to the receptors for chemoattractants and is expressed in the brain.

 

GPR45 is expressed in the forebrain, cerebral cortex, and liver (cells of cerebral cortex depicted below)

CEREBRUM

GPR48 is most highly expressed in the brain and pancreas and may relay signals through mechanisms that do not involve cAMP.

 

GPR49 is most highly expressed in skeletal muscle and may relay signals through mechanisms that do not involve cAMP.

 

GPR50 is similar to the melatonin receptor but does not bind melatonin.

 

GPR51 is expressed in the CNS and is similar to GABA receptors.

 

GPR52 is expressed in the caudate nucleus and the putamen.

 

GPR54 is the receptor for metastin which suppresses metastasis; it has a role in some thyroid cancers.

 

GPR55 is expressed in the caudate nucleus and the putamen.

 

GPR56 is most highly expressed in the thyroid and its expression changes in some melanomas.

 

GPR57 is expressed in the hippocampus but not in other regions of the brain.

 

GPR58 is expressed in the cerebellum but not in other regions of the brain

GPR61 is most similar to the amine receptors and is expressed only in the cerebellum.  The cerebellum is depicted below.

CEREBELLUM

GPR62 is expressed throughout the brain.

 

GPR63 is expressed in the brain.

 

GPR64 is specific to the epididymis (depicted in the following photo).

EPIDIDYMIS

GPR65 is expressed in lymphoid tissues.

 

GPR68 is expressed in various tissues.

 

GPR72 is similar to Y2 neuropeptide receptors.

 

GPR73 is a receptor for prokineticins which affect endothelial cells.

 

 Humans have homologs of the mamba MIT1 and the frog Bv8 peptides named prokineticin 1 and 2.  The 2 GPCR receptors, PK-R1 and PK-R2 are expressed in a variety of tissues (PK-2R in the CNS, Pk-1R in the testis, medulla, skeletal muscle, and skin (Soga, 2002).

 

GPR73L1 is a receptor for prokineticins which affect endothelial cells.

 

GPR75 is expressed in the CNS and in the eye.

 

GPR78 is expressed in the pituitary and the placenta.  The pituitary is pictured below.

PITUITARY

GPR80 is similar to purinoreceptors.

 

GPR81 is expressed in the pituitary but in no other region of the brain.

 

GPR82

 

GPR83

 

GPR84 is widely expressed.

 

GPR85 is most highly expressed in the brain and testis; zebrafish possess a homolog.

 

GPR86 is similar to P2Y12 and is most highly expressed in the spleen and brain.

 

GPR87 is similar to P2Y12 and is most highly expressed in the prostate but is also expressed in the uterus and testes.

 

GPR88 is expressed in the brain, especially in the basal nuclei.

 

GPR91

 

GPR92

 

GPR101 is expressed in the caudate nucleus and hypothalamus.

 

GPR102

 

GPR103 is similar to neuropeptide receptors.

 

GPRC5D is expressed most highly in the pancreas.

 

GPR 100, 119, 120, 135, 136, 141, 142 are members of the rhodopsin family without known close relatives, most of which are orphan receptors (Fredriksson, 2003).

 

Endocrine Portion of a frog pancreas.

PANCREAS

MAJOR HORMONES WHOSE RECEPTORS ARE GPCRs

     The signals that GPCRs respond to include many major circulating hormones.  Although there is a great diversity of distinct hormones in the human body (such as those which allow the human body to respond to changing calcium levels, mediate the stress response, determine skin pigmentation and hair, control blood glucose levels, stimulate gamete production, etc.), their effects are mediated through receptors which belong to the same gene family.

 

--ACTH

MC2R mutations can result in glucocorticoid deficiencies.

 

Receptors for anti-Muellerian hormone, which is secreted by the fetal testis to cause the degeneration of the ducts which would otherwise develop into the uterus and oviduct.

 

Calcitonin Receptor polymorphisms can affect bone density.

CALCRL  is expressed in smooth muscle (pictured below) and is decreased in pregnancy induced hypertension.

SMOOTH MUSCLE

CRH receptors are involved in the regulation of our responses to stress and their mutations can affect response to stress.

CRHR1 mutations in mice affect alcohol intake in response to stress.

 

CRHR2 affects anxious behavior in mice in males but not females.

 

FSHR is the receptor for FSH.  Receptor variants cause ovarian failure, ovarian tumors, and can be linked to the incidence of dizygotic twinning.

 

GIPR is the receptor for gastric inhibitory peptide and mutations affect obesity and glucose uptake.

 

GnRH receptor mutations cause hypogonadism. Although both tunicates and vertebrates both have duplicate gonadotropin releasing hormone receptors, they have arisen from independent duplications (Kusakabe, 2002).  While many vertebrates possess multiple GnRH receptor genes (including fish, amphibians, and many placental mammals), humans and chimp share one functional gene and one pseudogene (Morgan, 2004).

 

Glucagon Receptor.  Glucagon is secreted by the endocrine cells of the pancreas and increases blood glucose levels.

 

GHRHR mediated the response of growth hormone releasing hormone which increases the pituitary gland’s secretion of growth hormone.

 

LHR mutations in the receptor can cause precocious puberty and male pseudohermaphroditism.

 

Melatonin

MTNR1A receptors are expressed in the brain and mediate melatonin’s effects on ciradian rhythms and reproduction.

 

MTNR1B is expressed primarily in the retina (retina below; note melanin-rich layer).

RETINA

MSH (melanocortin)

     There are two types of melanin in humans: black eumelanin and red pheomelanin.  While eumelanin offers protection from UV light, pheomelanin does not (and might even contribute to cancers in that it may generate free radicals after exposure to UV light).  Different alleles of the MC1R receptor result in red hair and also blond/light brown hair.  Variations in this receptor are also associated with the inability to tan and the increased risk of melanoma.

The GPCR MC1R melanocortin receptor on melanocyte membranes is a factor in determining whether eumelanin (brown to black) or pheomelanin (red to yellow) is made. The hormomes α MSH and ACTH can stimulate the MC1R receptor. MSH increases the expression of the enzyme tyrosinase which increases the amount of brown-black pigment made. Another protein, the agouti signaling protein ASIP, can also bind the MC1R receptor, which blocks the action of MSH and results in the production of pheomelanin. The gene locus which contains the MC1R gene, known as the extension locus, is responsible for the production of the two types of melanin in mammals and birds (Makova, 2005).

Among Europeans, the average nucleotide difference in the coding region of this gene is much higher than at most other genome regions. The variant of Arg163Gln is at a very high frequency in East Asian and Native American populations. Fewer polymorphisms have been found in Africans which is unusual; given that human originated in Africa, it is typically observed that genetic diversity is highest among African populations. The 6.6 kb region upstream from the MC1R gene is one of the most variable nucleotide sequences in humans (Makova, 2005).

 MC1R variants can be associated with melanoma and UV damage to skin.

 

MC2R mutations cause glucocorticoid deficiencies.

 

MC3R is expressed in the brain, placenta, and GI tract.  One allele results in susceptibility to extreme obesity.


MC4R mutations are involved in obesity.

 

MC5R is expressed in a number of exocrine tissues.

 

--oxytocin

 

Parathormone of the parathyroid increases blood calcium concentrations by acting on osteoblasts, osteoclasts, the GI tract, and the kidney (human bone is pictured below).  Parathormone Receptor mutations can result in metaphyseal chodrodysplasia and enchodromatosis.

 

BONE

SCTR is the receptor for secretin and is expressed in the pancreas and intestine.

 

--TSH—mutations in the receptor can cause Graves disease, hyperthyroidism, and hypothyroidism.

 

Vasoactive intestinal peptide is a neuroendocrine peptide that can affect B and T cells.

VIP1

VIP2

 

Vasopressin (ADH)

AVPR1A receptors are expressed in the liver, smooth muscle, platelets and the brain.  In some mammals (such as voles) this receptor affects male reproduction and social behavior.  It is involved in platelet responses, cell division, and glycogenolysis.

 

AVPR1B is expressed in the kidney and mutations cause diabetes insipidis.

 

 

LOCAL HORMONES WHOSE RECEPTORS ARE GPCRs

     In addition to circulating hormones, which are synthesized in an endocrine tissue, diffuse into the blood, and which effect target cells which are often quite distant from where they were synthesized, the signals of the body include a large number of local hormones which only effect those cells which are located close to the cells which secrete the hormones.  For example, signals which mediate inflammation and the response of white blood cells to infection are local signals.  The effects of these local hormones are mediated through G protein coupled receptors.

 

Bradykinin secretion is involved in inflammation, pain, muscle tension, and bronchoconstriction.

BDKRB1 is involved in the response to tissue injury and in chronic inflammation.

 

BDKRB2 is expressed in smooth muscle and is involved in inflammation and bronchoconstriction.

 

HISTAMINE

     Histamine is produced by mast cells, basophils, enterochromaffin cells, and neurons.

HRH1 is expressed in neurons, the stomach, in muscle, and on T helper cells.  Mutations result in abnormal functioning of the GI tract and the nervous system.

 

HRH2 has a distribution similar to HRH1.

 

HRH3 is expressed in the CNS and PNS.

 

HRH4 is expressed in the hippocampus, lung, and cerebellum

CELLS

INTERLEUKINS

Interleukins form a family of local hormones which are important signals for immune cells, such as the leukocytes of a lymph node pictured above.  Their receptors form a family of GPCRs.  The interleukins are numbered (IL1, IL2, IL3, etc.) and their receptors maintain this numbering (ILR1, ILR2, ILR3, etc.). 

IL1R1

IL1RL1

IL1RL2 seems to promote growth of some cells.

IL2RA possesses 2 fibronectin domains.

IL2RB prevents autoimmunity and controls T cells.

IL2RG can form heterodimers with IL2RB and heterotrimers with IL2A and B.

Most T cells lack IL2 receptors and, as a result, there is no uncontrolled T-cell proliferation in response to inflammatory signals.

IL3RA is involved in hematopoeisis.

IL4R mediates the effects of interleukin 4 which is secreted by T cells to promote cell growth.  Mutations in the receptor cause atopic asthma and the increased IgE levels observed in atopy.

IL5RA is involved in eosinophil activity and B cell development.  An eosinophil is pictured below.

EOSINOPHIL

IL6R possesses an immunoglobulin-like domain.

IL7R is involved in lymphopoeisis.

IL8RA and IL8RB mediate the effects of interleukin 8 which is used in inflammation and tissue repair.

IL8RB

IL9R promotes growth in T cells, mast cells, and some hematopoeitic cells; it is involved in the growth of some tumors.

IL10RA

IL10RB

IL12RA is involved in the formation of white blood cells.

IL12RB1 mutations increase susceptibility to mycobacterium and Salmonella infections.

IL12RB2 is expressed in T cells.

IL13RA1 mutations increase production of IgE.

IL13RA2

IL15RA is not essential in itself, but it affects the binding of other factors to their receptors.

IL17R is involved in hematopoeisis.

IL17BL is produced in a number of fetal tissues and in adult endocrine tissues.

IL18R1 is expressed in a number of tissues.

IL20RA is more highly expressed in psoriatic skin.

IL20RB is more highly expressed in psoriatic skin.

IL21R

IL22R

 

LEUKOTRIENES

Cysteine leukotriene receptors 1 and 2 are expressed, among other places, in the smooth muscle of the lung and are involved in asthma and analyphylactic responses.

 

CYSTLTR1

 

CYSTLTR2

 

LTB4R is involved in inflammation and immune responses.

 

 

PROSTAGLANDINS

Arachidonic acid can be modified to produce a set of local hormones called prostanoids which function in inflammation, blood clotting, and vasoconstriction.  They were first isolated from the prostate after animal experiments which measured the decrease in blood pressure after injecting semen into animal bloodstreams.  A number of prostaglandins (PGD< PGE, PGI, and PGF) and thromboxanes (TxA and TxB) are known.  Prostanoids activate G-protein coupled receptors related to rhodposin which form a subfamily (EP1, EP2, EP3,and EP4) (Bos, 2004).

 

PTGFR interacts with factors which can determine the timing of birth.  Mutant mice can’t deliver their fetuses and there is no response to oxytocin.

 

PTGDR is involved in basophil and eosinophil migration.

 

PTGIR

 

PTGER1 expression is increased in some cancers.

 

PTGER2 receptors are related to thromboxane (a clotting factor) receptors (which is not surprising since prostaglandin PGF2 is homologous to thromboxane).  Mutations in mice cause infertility.

 

PTGER3

 

PTGER4 is expressed in the lung, lymph nodes, and in blood vessels.  Expression increases in some cancers and mutant mice lacking this receptor die (lung tissue below).

LUNG

PTGFRN

 

Chemokines are local hormones that have roles in development, homeostasis, angiogenesis, and immune function.  Their receptors are divided into subfamilies which can be represented by the relationship of cysteine amino acids and the number of amino acids which separate 2 cysteine residues (C, CC, CXC, CXXC). Polymorphisms in the genes for cytokines, chemokines, and their receptors (such as CCR5, CCR2, CX3CR1, SDF1, MIP1α, RANTES, IL-10, IL-4) are responsible for some of the difference in susceptibility to HIV infection (Telenti, 2005).

 

CCR1 is involved in the systemic inflammatory response syndrome.

 

CCR2 is a receptor for MCP1, the monocyte chemoattractant protein.  One allele of this receptor offers resistance from HIV.

 

CCR3 is the receptor for eotaxin and is expressed on eosinophils.

 

CCR4 is expressed on leukocytes and in the thymus.

 

CCR5 is a coreceptor for HIV.  Different alleles affect the progression of AIDS and some alleles offer resistance to HIV.

 

CCR6 binds b defensin and is expressed on dendritic cells and memory T cells.

 

CCR7 is expressed on memory T cells which localize to lymph nodes and stimulate dendritic cells.  Memory T cells which lack this receptor travel to inflamed tissues.

 

CCR8 affects eosinophil movement.

CCR9 is expressed on memory T cells and responds to a chemokine produced in the thymus.

 

CCRL1 is expressed throughout the body.

 

CXCR4 is a coreceptor for HIV and is involved in atherosclerosis.  One allele causes a rapid progression of AIDS.  The chemokine receptors CXCR4 and CCR5 serve as coreceptors for HIV and SIV viruses.  In general, specific white blood cells are activated by the interaction of their chemokine receptors and the chemokine ligands and this interaction can regulate their migration.  These receptors can mediate the fusion of uninfected white blood cells with infected cells expressing the env protein of HIV and SIV viruses.  Sequence similarities suggest that these chemokine receptors and the env protein of HIV/SIV viruses may have a common origin (Shimizu, 2000; OMIM).

     Cxcr4 is required for normal chemotaxis of primordial germ cells in embryonic development.  The homologue of the chemokine receptor Cxcr4 in zebrafish functions in development for the migration of germ cells (Knaut, 2003). 

 

 

CX3CR1 is a receptor for neuropeptide Y which affects embryonic development, the bone marrow, leukocytes, and the migration of embryonic cells.  It is expressed in the immune and nervous systems.

 

CX3R3 is expressed on some memory T cells.

 

CCXCR1 is expressed in the placenta, spleen, and thymus.  Cells of the thymus are depicted below.

LYMPH

CXCR1

 

CMKLR1 is expressed in the brain and cardiovascular system.

 

The Duffy blood group comprises variations of a chemokine receptor expressed on red blood cells. Since the malaria parasite enters red blood cells through this receptor, Duffy negative homozygous humans which do not produce this receptor are not susceptible to malaria (Escalante, 2005; Chaudhuri, 1994).

PURINERGIC RECEPTORS

    The types of molecules which can be used in signaling include nucleotides and there are CPCRs which can respond to nucleotide signals, all but one respond to purine nucleotides.  (There are other receptors for purines which are not G-protein coupled receptors.)  P1 purinoceptors respond to adenosine while P2 purinoceptors respond to ATP, UTP, and UDP.   P2X receptors possess an ion channel while P2Y receptors are GPCRs.  P2Y receptors are involved in smooth muscle relaxation, hormone secretion, immunity, cell division, and communication between neurons and glia.  The five known branches of this gene family appear to have arisen from gene duplication (Somers, 1997).

 

P2RY1 is expressed in platelets and megakaryoblasts.

 

P2RY2 is involved in chloride ion transport through a mechanism which bypasses the channel mutated in cystic fibrosis.  It is expressed in the ovary.

 

P2RY11 is most highly expressed in the spleen.

 

P2RY12 is the platelet receptor for ADP which causes them to change their shape and inhibit adenylate cyclase.  Mutations can result in a bleeding disorder.

 

P2RY4 binds to UTP and UDP and is thus a pyrimidinergic receptor.

 

OTHER

 

--adenosine—adenosine is used as a signal in the a variety of tissues, including the CNS.

 

ADORA1 is expressed in the CNS, the GI tract, and other tissues; it is involved in the capacitation of sperm.

 

ADORA2A is expressed in the basal ganglia, platelets, and blood vessels.  Caffeine affects its activity.

 

ADORA2B is involved in the growth of dorsal spinal cord axons and in the development of retinal  blood vessels.

 

ADORA3 is expressed in the ventricles of the heart where it protects muscle cells.

 

ADORA2L1

 

--angiotensin

The utilization of a rennin-angiotensin system to maintain blood pressure is conserved in amphibians through mammals as are the angiotensin receptors which mediate the changes (Sandberg, 2001).  In general, mammals possess two angiotensin receptors, although a duplication of the AT1 receptor is known in rodents (Sandberg, 2001).

 

AGTR1 mutations affect blood pressure and in mice have been shown to be involved in angiogenesis.

 

AGTR2 mutations increase blood pressure and can result in mental retardation.  Although it is only expressed in some adult tissues (including the brain), it is widely expressed in fetal tissues.

 

AGTRL1 is expressed in the brain.

 

AGTRL2

 

The Burkitt lymphoma receptor is involved in lymphocyte migration.

 

C3AR1 is the receptor for complement component 3a which is part of immune complement system and is involved in anaphylatoxins response, cytokine release, and chemotaxis.

 

Endothelin

ENDRA alleles can affect resistance to migraines.

 

ENDRB mutations cause Hirschsprung disease type 2 which affects pigmentation, produces a white forelock, and causes hearing loss.

 

Receptors for endothelial differentiation genes affect smooth muscle contraction and platelet aggregation.

 

Formyl Peptide

FPR1 is the receptor for formyl peptide which attracts neutrophils.

 

FPRL1 is expressed in embryonic kidney cells and is involved in the response of brain cells to prion proteins and neutrophils to aspirin.  The embryonic  kidney cells of a pig are depicted below.

METANEPHROS

FPRL2

 

Receptors GLP1R and GLP2R respond to glucagon-like peptide 2 which stimulates intestinal growth and increases villus height

 

SCTR is the receptor for growth hormone secretagogue which increases growth hormone secretion.

 

ADCYAP1R1 is the receptor for pituitary adenylate cyclase activating peptide which is secreted from the hypothesis, pituitary, pancreas, and testes.  Its receptor is secreted in the CNS and GI tract.

 

Receptors for platelet aggregation factors

 

PTAFR is the receptor for platelet activating factor which is involved in allergies, asthma, septic shock, arterial thrombosis, and inflammation.

 

Platelet thrombin receptor

 

 Many GPCRs are referred to as “orphan” GPCRs because their ligands are unknown.  Their characterization will help in the search for their endogenous ligands, which seem to include both peptides and undiscovered amine-like transmitters.  The analysis of one amine-like GPCR led to the discovery of a closely related receptors in zebrafish, mice, and humans referred to as Super Conserved Receptor Expressed in Brain (SREB).  Humans have at least 3 SREB genes expressed in the nervous system, SREB1, SREB2, and SREB3 (Matsumoto, 2000).

SREB1

SREB2

SREB3

 

 

     PSP24 homologs are known in humans, mice, and frogs.  In mice they are expressed in the hippocampus, cerebral cortex, cerebellum, and olfactory regions (Kawasawa, 2000).

 

     LGR7 and LGR8 were formerly classified as orphan receptors but are now known to serve as receptors for relaxin.  They are similar to gonadotropin and thryrotropin receptors (Hsu, 2003).

 

The GPCR MRGX2 functions in the perception of pain.  The higher than expected variation between human and chimp genes implies that it has experienced selective forces (Yang, 2005).

 

 

 

 

 

 

Hydra contain two ras genes, one of which is involved in the development of the head (Boschm, 1995)

 

The non-genomic effects of steroid hormones in fish are mediated through GPCRs (Thomas, 2006).