GPR65

Key takeaways

GPR65 belongs to biology; place it in that map before memorising details.
Learn the definition first, then one example that makes the definition concrete.
Connect GPR65 to a quantity you can measure, compute or draw — that is where exam questions come from.
Reproduce the core statement of GPR65 from memory before moving on to harder problems.

Reference excerpt

Psychosine receptor is a G protein-coupled receptor (GPCR) protein that in humans is encoded by the GPR65 gene. 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. 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)methylsulfanyl]-1,6-dimethylpyridazino[4,5-e][1,3,4]thiadiazin-5-one (referred to as BTB09089) was found to be a specific agonist for GPR65. Furthermore, [(S)-phenyl(pyridin-4-yl)methyl] 4-methyl-2-pyrimidin-2-yl-1,3-thiazole-5-carboxylate (referred to as ZINC62678696) was found to act as a BTB09089 negative allosteric modulator.

pH sensing GPR65 senses extracellular pH. Levels of cyclic adenosine monophosphate (cAMP), a secondary messenger associated with activation of GPCRs in the cAMP-dependent pathway, 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 increased at a shifted, more acidic pH range. As such, psychosine displayed an inhibitory effect as an antagonist when GPR65 was stimulated with an increasing concentration of protons (increasingly acidic pH). This finding directly contested the previous reporting of psychosine as an activating ligand for GPR65. The pH-sensing ability of GPR65 was further tested and confirmed, as it was found that cAMP levels increased when GPR65 was stimulated by pH values less than pH 7.2. GPR65 senses pH by protonation of histidine 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 development. GPR65 is highly expressed in a variety of human tumors. Tumor development is associated with low extracellular pH due to changes in metabolism 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 production of T cells (including IL-6, TNF-α and IL-1β) and macrophages.

Cardiovascular After myocardial infarction, anaerobic respiration and severe inflammation occurs—both of which are accompanied by an acidic environment. GPR65 knockout mice 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.

See also Proton-sensing G protein-coupled receptors

References

Illustrations

Worked examples

Example 1 — a first encounter with GPR65

Start with the simplest possible case. Write down what GPR65 claims or describes in one sentence, then invent the smallest concrete situation in which that sentence is true. In biology, the smallest case is usually a single object, a single equation or a single measurement. Check that every symbol or term in your sentence has a meaning in that case.

Example 2 — changing one variable

Take the situation from Example 1 and change exactly one quantity: double it, halve it, or set it to zero. Predict what should happen to GPR65 before you calculate. Comparing your prediction with the result is the fastest way to find out whether you understand the idea or only the words.

Example 3 — an exam-style question

Typical questions about GPR65 ask you to (a) state it precisely, (b) apply it to given data, and (c) explain a limitation. Practise writing all three answers in under five minutes; the third part is what separates a full-mark answer from an average one.

Applications of GPR65

In research: GPR65 appears in biology research whenever the underlying quantities have to be modelled precisely. Papers usually cite it as a starting assumption and then explore where it breaks down.
In technology and industry: Engineering practice reuses GPR65 in design rules, simulations and safety margins. Knowing the idea lets you read a specification sheet and understand why the numbers look the way they do.
In the classroom: GPR65 is common in secondary-school and first-year university syllabi. It links to neighbouring topics G protein-coupled receptors, Genes on human chromosome 14, so understanding it makes those chapters shorter.
In everyday life: Look for GPR65 outside the textbook — in sport, cooking, traffic, electronics or the sky above you. An example you found yourself is remembered far longer than one you were given.

How to study GPR65 in 20 minutes

Read the reference excerpt below once, without taking notes.
Close the page and write down what GPR65 means in your own words.
Compare your version with the excerpt and mark what you missed.
Work through the three examples above with pen and paper.
Explain GPR65 out loud to somebody else — or to Teacher Smith in the lgStudy chat.

Frequently asked questions

What is GPR65 in simple terms?

Psychosine receptor is a G protein-coupled receptor (GPCR) protein that in humans is encoded by the GPR65 gene. GPR65 is also referred to as TDAG8.

Why does GPR65 matter?

Because it connects several biology ideas at once: it gives you a definition you can apply, a quantity you can calculate, and a way to check whether a result is plausible.

How should I study GPR65?

Read the excerpt, restate it from memory, then work through the examples and applications listed on this page. The five-step study plan above takes about twenty minutes.

What does this page cover?

It gives you a compact reference excerpt plus original lgStudy explanations, examples, applications and study material on GPR65.