Psychosine receptor is a

G protein-coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily related ...

(GPCR)

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

that in humans is encoded by the ''GPR65''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. GPR65 is also referred to as TDAG8.

Species, tissue, and subcellular distribution

GPR65 (TDAG8) is primarily expressed in lymphoid tissues (spleen, lymph nodes, thymus, and leukocytes), and as a GPCR, the protein is localized to the plasma membrane.

Function

Ligand binding

In 2001, GPR65 was reported to be a specific receptor for psychosine (d-galactosyl-β-1,1′ sphingosine) as well as several other related

glycosphingolipids Glycosphingolipids are a subtype of glycolipids containing the amino alcohol sphingosine. They may be considered as sphingolipids with an attached carbohydrate. Glycosphingolipids are a group of lipids (more specifically, sphingolipids) and are a p ...

. However, the specific binding of psychosine to GPR65 has been contested as the reported ligand binding did not satisfy the appropriate pharmacological criteria. More recently, 3- 2,4-dichlorophenyl)methylsulfanyl1,6-dimethylpyridazino ,5-e1,3,4]thiadiazin-5-one (referred to as BTB09089) was found to be a specific agonist for GPR65. Furthermore, S)-phenyl(pyridin-4-yl)methyl4-methyl-2-pyrimidin-2-yl-1,3-thiazole-5-carboxylate (referred to as ZINC62678696) was found to act as a BTB09089 negative

allosteric modulator In pharmacology and biochemistry, allosteric modulators are a group of substances that bind to a receptor to change that receptor's response to stimuli. Some of them, like benzodiazepines or alcohol, function as psychoactive drugs. The site that a ...

pH sensing

GPR65 senses extracellular pH. Levels of

cyclic adenosine monophosphate Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-cyclic adenosine monophosphate) is a second messenger, or cellular signal occurring within cells, that is important in many biological processes. cAMP is a derivative of adenosine tri ...

(cAMP), a

secondary messenger Second messengers are intracellular signaling molecules released by the cell in response to exposure to extracellular signaling molecules—the first messengers. (Intercellular signals, a non-local form of cell signaling, encompassing both first m ...

associated with activation of GPCRs in the

cAMP-dependent pathway In the field of molecular biology, the cAMP-dependent pathway, also known as the adenylyl cyclase pathway, is a G protein-coupled receptor-triggered signaling cascade used in cell communication. Discovery cAMP was discovered by Earl Sutherla ...

, were found to be elevated in neutral to acidic extracellular pH (pH 7.0-6.5) in cells expressing GPR65. In cells with mutated GPR65, this pH-sensing effect was reduced or eliminated. In the presence of psychosine, however, the levels of

cAMP Camp may refer to: Areas of confinement, imprisonment, or for execution * Concentration camp, an internment camp for political prisoners or politically targeted demographics, such as members of national or minority ethnic groups * Extermination ...

increased at a shifted, more acidic pH range. As such, psychosine displayed an inhibitory effect as an

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.psychosine as an activating ligand for GPR65. The pH-sensing ability of GPR65 was further tested and confirmed, as it was found that

levels increased when GPR65 was stimulated by pH values less than pH 7.2. GPR65 senses pH by protonation of

histidine Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an Amine, α-amino group (which is in the protonated –NH3+ form under Physiological condition, biological conditions), a carboxylic ...

residues on its extracellular domain, and when activated, GPR65 enables the downstream signaling through the Gq/11, Gs, and G12/13 pathways. The ability of GPR65 to sense pH can modulate several cellular functions in various biological systems including the immune, cardiovascular, respiratory, renal, and nervous systems. GPR65's ability to sense pH plays a prominent role in

tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

development. GPR65 is highly expressed in a variety of human tumors. Tumor development is associated with low extracellular pH due to changes in

metabolism Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

of rapidly dividing cells. GPR65 enables tumor growth by sensing the acidic environment. It was found that overexpression of GPR65 prevents tumor cell death in acidic conditions in vitro and facilitates tumor growth in vivo.

Immune

GPR65 reduces immune-mediated inflammation by regulating

cytokine Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...

production of

T cells T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their ce ...

(including IL-6, TNF-α and IL-1β) and

macrophages Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...

Cardiovascular

After

myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when Ischemia, blood flow decreases or stops in one of the coronary arteries of the heart, causing infarction (tissue death) to the heart muscle. The most common symptom ...

, anaerobic respiration and severe inflammation occurs—both of which are accompanied by an acidic environment. GPR65

knockout mice A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or " knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importan ...

showed a decline in survival and cardiac function after myocardial infarction, which indicates that GPR65-mediated pH sensing is physiologically relevant. GPR65 exhibits a cardioprotective effect against myocardial infarction by reducing CCL20 expression and the migration of IL-17A-producing γδT cells that express CCR6, a receptor for CCL20.

Visual

Retinal function is sensitive to changes in pH. It was found that GPR65 is overexpressed in the retina of mouse models of retinal degeneration and that the receptor supports the survival of photoreceptors in a degenerating retina by sensing pH and activating microglia after light-injury.

Gastrointestinal

Vagal afferents expressing GPR65 innervate intestinal villi. These GPR65-expressing vagal afferents detect nutrients in the intestinal lumen and also slow gut motility.

Depression

GPR65 was identified as a potential target linking inflammation and depression. GPR65 knockout mice exhibited a significant reduction in mobility in a forced swim test as well as higher consumption of sucrose—both of which are behaviors associated with depression.

History/Discovery

In 1996, Choi et al. first identified GPR65 (TDAG8) as a G protein-coupled receptor whose expression was induced during activation-induced apoptosis of T cells. The group sought to identify which genes were necessary during T cell receptor-mediated death of immature thymocytes, and using differential mRNA display, they found that TDAG8 expression was induced upon activation of T cells. Because this gene was found to be associated with T-cell death (apoptosis), it was named TDAG8, or T Cell Death Associated Gene 8.