SII-SWORD/CoKE huggingface dataset:
EDG-8 sphingosine 1-phosphate receptor (EDG8_S1P_rcpt)
Type: Family

G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups . The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence . The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) . GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice . Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs .

The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices .

Sphingosine 1-phosphate (S1P) is released from activated platelets and is also produced by a number of other cell types in response to growth factors and cytokines . It is proposed to act both as an extracellular mediator and as an intracellular second messenger. Recently, 5 G protein-coupled receptors have been identified that act as high affinity receptors for S1P and also as low affinity receptors for the related lysophospholipid, SPC . EDG-1, EDG-3, EDG-5 and EDG-8 share a high degree of similarity and are also referred to as lpB1, lpB3, lpB2 and lpB4, respectively. EDG-6 is referred to as lpC1, reflecting its more distant relationship to the other S1P receptors.

EDG-8 is expressed predominantly in the white matter tracts of the brain and in the pancreas . Upon binding of S1P, EDG-8 appears to couple to Gi and G12 proteins but not Gq family members. Unlike other EDG receptors, which activate MAP kinases and stimulate proliferation, EDG-8 causes inhibition of ERK MAP kinases and proliferation, and also inhibition of adenylyl cyclase .
CX3C chemokine receptor 1 (Chemokine_CX3CR1)
Type: Family

Chemokines (chemotactic cytokines) are a family of chemoattractant molecules. They attract leukocytes to areas of inflammation and lesions, and play a key role in leukocyte activation. Originally defined as host defense proteins, chemokines are now known to play a much broader biological role . They have a wide range of effects in many different cell types beyond the immune system, including, for example, various cells of the central nervous system , and endothelial cells, where they may act as either angiogenic or angiostatic factors .

The chemokine family is divided into four classes based on the number and spacing of their conserved cysteines: 2 Cys residues may be adjacent (the CC family); separated by an intervening residue (the CXC family); have only one of the first two Cys residues (C chemokines); or contain both cysteines, separated by three intervening residues (CX3C chemokines).

Chemokines exert their effects by binding to rhodopsin-like G protein-coupled receptors on the surface of cells. Following interaction with their specific chemokine ligands, chemokine receptors trigger a flux in intracellular calcium ions, which cause a cellular response, including the onset of chemotaxis. There are over fifty distinct chemokines and least 18 human chemokine receptors . Although the receptors bind only a single class of chemokines, they often bind several members of the same class with high affinity. Chemokine receptors are preferentially expressed on important functional subsets of dendritic cells, monocytes and lymphocytes, including Langerhans cells and T helper cells . Chemokines and their receptors can also be subclassified into homeostatic leukocyte homing molecules (CXCR4, CXCR5, CCR7, CCR9) versus inflammatory/inducible molecules (CXCR1, CXCR2, CXCR3, CCR1-6, CX3CR1).

The only CX3C chemokine identified to date is CX3C chemokine ligand 1 (CX3CL1), also known as fractalkine or neurotactin. It is a transmembrane molecule containing a chemokine domain on an extended mucin-like stalk .

Both the adhesive and chemotactic effects of CX3CL1 are mediated through CX3C chemokine receptor type 1 (CX3CR1), also known as fractalkine receptor . The receptor is expressed specifically on T cells, natural killer cells and monocytes . Coupling of the receptor to pertussis toxin-sensitive Gi proteins leads to calcium mobilisation and chemotaxis . In contrast, adhesion mediated by the receptor is insensitive to pertussis toxin and does not appear to involve calcium mobilisation. CX3CR1 has also been found to act as a weak fusion cofactor for some HIV-1 strains, an interaction that can be potently and specifically blocked by CX3CL1 .
G2A lysophosphatidylcholine receptor (G2A_lysphc_rcpt)
Type: Family

G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups . The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence . The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) . GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice . Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs .

The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices .

G2A is expressed mainly in lymphocytes and its expression is up-regulated by stress and prolonged mitogenic signals. Mice lacking the receptor have been found to develop a late-onset autoimmune disease . It has therefore been suggested that G2A may function as a sensor of LPC levels at sites of inflammation and act as a negative regulator of lymphocyte growth to limit expansion of tissue-infiltrating cells and overt autoimmune disease. Activation of G2A by LPC results in an increase in intracellular calcium levels (through coupling to Gi proteins) and activation of MAP kinases. The receptor has also been shown to couple to G13 proteins, causing RhoA activation and formation of actin stress fibres.
OGR1 sphingosylphosphorylcholine receptor (OGR1_rcpt)
Type: Family

G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups . The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence . The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) . GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice . Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs .

The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices .

OGR1 is expressed in ovarian cancer cell lines and also in spleen, testis, small intestine, peripheral blood leukocytes, brain, heart, lung, placenta and kidney. Expression has not been found in thymus, prostate, ovary, colon, liver, skeletal muscle or pancreas .
Neuromedin U receptor (NeuromedU_rcpt)
Type: Family

G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups . The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence . The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) . GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice . Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs .

The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices .

Neuromedin U is a neuropeptide, first isolated from porcine spinal cord and expressed widely in the gastrointestinal, genitourinary and central nervous systems . Neuromedin U has potent contractile activity on smooth muscle and this activity is believed to reside within the C-terminal portion of the peptide, which is highly conserved between species. Other roles for the peptide include: regulation of blood flow and ion transport in the intestine, regulation of adrenocortical function and increased blood pressure . The roles of neuromedin U in the central nervous system are poorly understood, but may include: regulation of food intake, neuroendocrine control, modulation of dopamine actions and involvement in neuropsychiatric disorders. Two G protein-coupled receptor subtypes, with differing expression patterns, have been identified and shown to bind neuromedin U.
Neuromedin U receptor, type 2 (NeuromedU_rcpt_2)
Type: Family

G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups . The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence . The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) . GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice . Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs .

The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices .

Neuromedin U is a neuropeptide, first isolated from porcine spinal cord and expressed widely in the gastrointestinal, genitourinary and central nervous systems . Neuromedin U has potent contractile activity on smooth muscle and this activity is believed to reside within the C-terminal portion of the peptide, which is highly conserved between species. Other roles for the peptide include: regulation of blood flow and ion transport in the intestine, regulation of adrenocortical function and increased blood pressure . The roles of neuromedin U in the central nervous system are poorly understood, but may include: regulation of food intake, neuroendocrine control, modulation of dopamine actions and involvement in neuropsychiatric disorders. Two G protein-coupled receptor subtypes, with differing expression patterns, have been identified and shown to bind neuromedin U.

The neuromedin U type 2 receptor (NMU2) is expressed most abundantly in the central nervous system, particularly in the medulla oblongata, pontine reticular formation, substantia nigra, spinal cord and thalamus . High levels of expression have also been found in the thymus, thyroid and testes . NMU2 has been detected at much lower levels in some peripheral tissues, including the kidney, lung, trachea and gastrointestinal tract.
XC chemokine receptor 1 (Chemokine_XCR1)
Type: Family

Chemokines (chemotactic cytokines) are a family of chemoattractant molecules. They attract leukocytes to areas of inflammation and lesions, and play a key role in leukocyte activation. Originally defined as host defense proteins, chemokines are now known to play a much broader biological role . They have a wide range of effects in many different cell types beyond the immune system, including, for example, various cells of the central nervous system , and endothelial cells, where they may act as either angiogenic or angiostatic factors .

The chemokine family is divided into four classes based on the number and spacing of their conserved cysteines: 2 Cys residues may be adjacent (the CC family); separated by an intervening residue (the CXC family); have only one of the first two Cys residues (C chemokines); or contain both cysteines, separated by three intervening residues (CX3C chemokines).

Chemokines exert their effects by binding to rhodopsin-like G protein-coupled receptors on the surface of cells. Following interaction with their specific chemokine ligands, chemokine receptors trigger a flux in intracellular calcium ions, which cause a cellular response, including the onset of chemotaxis. There are over fifty distinct chemokines and least 18 human chemokine receptors . Although the receptors bind only a single class of chemokines, they often bind several members of the same class with high affinity. Chemokine receptors are preferentially expressed on important functional subsets of dendritic cells, monocytes and lymphocytes, including Langerhans cells and T helper cells . Chemokines and their receptors can also be subclassified into homeostatic leukocyte homing molecules (CXCR4, CXCR5, CCR7, CCR9) versus inflammatory/inducible molecules (CXCR1, CXCR2, CXCR3, CCR1-6, CX3CR1).

Chemokine XC receptor 1 (XCR1), which this entry represents is a receptor for lymphotactin . Lymphotactin is the only known member of the C (or XC) chemokine family, and is produced by certain subsets of T cells and natural killer cells and is also chemotactic for these cell types . XCR1 is strongly expressed in placenta and at lower levels in the spleen and thymus and detected only at very low levels in peripheral blood leukocytes . Within these tissues, expression is restricted to CD8+ T cells and natural killer cells . Binding of lymphotactin to XCR1 stimulates calcium mobilisation and migration in a pertussis toxin-sensitive manner, indicating coupling of the receptor to Gi type proteins . The matching expression patterns of both lymphotactin and its receptor suggest a role for the chemokine in self-recruitment of leukocytes .
P2Y12 purinoceptor (P2Y12_rcpt)
Type: Family

There are three distinct families of extracellular receptors for purine and pyrimidine nucleotides , known as P1, P2X and P2Y purinoceptors . These receptors induce a wide variety of biological effects and are involved in many different cellular functions . P2X receptors are ligand-gated ion channels, whereas P1 and P2Y receptors are rhodopsin-like G protein-coupled receptors . The families also differ by their method of activation: P1 receptors are preferentially activated by adenosine , P2X via ATP , whereas the P2Y receptors, in addition to being activated by ATP, are activated by different adenine and/or uridine nucleoside di- and triphosphates (ADP, UDP, UTP, UDP and UDP-glucose) .

The P2Y purinoceptors currently consist of eleven subtypes: P2Y1, P2Y2, P2Y3 P2Y4, P2Y6, P2Y8, P2Y10, P2Y11, P2Y12, P2Y13 and P2Y14 . P2Y3 has, as yet, only been found in birds , whilst the rest have been cloned in humans. The gaps in P2Y receptor numbering are due to the reclassification of some receptors that were initially associated with to the P2Y family. These include P2Y5 (now known as lysophosphatidic acid receptor 6), P2Y7 (now leukotriene B4 receptor) and P2Y9 (lysophosphatidic acid receptor 4) .

This entry represents the P2Y12 receptor. It is primarily activated by ADP and is coupled to Gi, inhibiting adenylate cyclase . The P2Y12 receptor is highly expressed on the surface of blood platelets where it plays a role in amplification of platelet activation and aggregation , and is thus a potential target for the treatment of thromboembolisms and other blood clotting disorders . The P2Y12 receptor is also expressed in the brain , glial cells , brain capillary endothelial cells and smooth muscle cells , although the precise role of this subtype in these tissues is not known.
Neuropeptide FF receptor family (NPFF_rcpt)
Type: Family

Neuropeptide FF receptors belong to a family of neuropeptides containing an RF-amide motif at their C terminus which have a high affinity for the pain modulatory peptide neuropeptide NPFF (NPFF) . Neuropeptide FF (NPFF) receptors have two subtypes, neuropeptide FF receptor type 1 (NPFF1) and neuropeptide FF receptor type 2 (NPFF2), they are members of rhodopsin G protein-coupled receptor family. The neuropeptide FF is found at high concentrations in the posterior pituitary, spinal cord, hypothalamus and medulla and is believed to be involved in pain modulation, opioid tolerance, cardiovascular regulation, memory and neuroendocrine regulation .

Comparing the distribution of NPFF1 and NPFF2 receptors in different species reveals important species differences . The NPFF1 receptor is broadly distributed in the central nervous system with the highest levels found in the limbic system and the hypothalamus, is thought to participate in neuroendocrine functions. Whereas as the NPFF2 receptor is present in high density, particularly in mammals in the superficial layers of the spinal cord where it is involved in nociception and modulation of opioid functions , consistent with a potential role of NPFF in the modulation of sensory inputs, like pain responses .

This entry represents the neuropeptide FF receptor family.
Neuropeptide FF receptor, type 1 (NPFF_rcpt_1)
Type: Family

Neuropeptide FF receptors belong to a family of neuropeptides containing an RF-amide motif at their C terminus which have a high affinity for the pain modulatory peptide neuropeptide NPFF (NPFF) . Neuropeptide FF (NPFF) receptors have two subtypes, neuropeptide FF receptor type 1 (NPFF1) and neuropeptide FF receptor type 2 (NPFF2), they are members of rhodopsin G protein-coupled receptor family. The neuropeptide FF is found at high concentrations in the posterior pituitary, spinal cord, hypothalamus and medulla and is believed to be involved in pain modulation, opioid tolerance, cardiovascular regulation, memory and neuroendocrine regulation .

Comparing the distribution of NPFF1 and NPFF2 receptors in different species reveals important species differences . The NPFF1 receptor is broadly distributed in the central nervous system with the highest levels found in the limbic system and the hypothalamus, is thought to participate in neuroendocrine functions. Whereas as the NPFF2 receptor is present in high density, particularly in mammals in the superficial layers of the spinal cord where it is involved in nociception and modulation of opioid functions , consistent with a potential role of NPFF in the modulation of sensory inputs, like pain responses .

This entry represents NPFF1 receptor, which is expressed at highest levels in the hypothalamus, with moderate expression in the thalamus, midbrain, medulla oblongata, testis and eye . NPFF1 receptor has been found to regulate adenylyl cyclase in some recombinant cell lines . It also couples with Gi protein to inhibit adenylyl cyclase (AC) , and reduces the activities of cAMP-dependent protein kinase (PKA) and mitogen-activated protein kinase (MAPK) signaling cascade.