G protein-coupled receptor 35 also known as GPR35 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 ...
which in humans is encoded by the ''GPR35''
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 ...
. Heightened expression of GPR35 is found in immune and gastrointestinal tissues, including the
crypts of Lieberkühn
In histology, an intestinal gland (also crypt of Lieberkühn and intestinal crypt) is a gland found in between villi in the intestinal epithelial lining of the small intestine and large intestine (or colon). The glands and intestinal villi are ...
.
Ligands
Endogenous ligands
Although GPR35 is still considered an
orphan receptor
In biochemistry, an orphan receptor is a protein that has a similar structure to other identified receptors but whose endogenous ligand has not yet been identified. If a ligand for an orphan receptor is later discovered, the receptor is referred ...
, there have been attempts to deorphanize it by identifying
endogenous
Endogeny, in biology, refers to the property of originating or developing from within an organism, tissue, or cell.
For example, ''endogenous substances'', and ''endogenous processes'' are those that originate within a living system (e.g. an ...
molecules that can activate the receptor. All of the currently proposed ligands are either unselective towards GPR35, or they lack high
potency
Potency may refer to:
* Potency (pharmacology), a measure of the activity of a drug in a biological system
* Virility
* Cell potency, a measure of the differentiation potential of stem cells
* In homeopathic dilutions, potency is a measure of ho ...
, a characteristic feature of natural ligands. The following list includes the most prominent examples:
*
kynurenic acid
Kynurenic acid (KYNA or KYN) is a product of the normal metabolism of amino acid -tryptophan. It has been shown that kynurenic acid possesses neuroactive activity. It acts as an antiexcitotoxic and anticonvulsant, most likely through acting as an ...
cyclic guanosine monophosphate
Cyclic guanosine monophosphate (cGMP) is a cyclic nucleotide derived from guanosine triphosphate (GTP). cGMP acts as a second messenger much like cyclic AMP. Its most likely mechanism of action is activation of intracellular protein kinases in ...
agonists
An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the agon ...
of GPR35 include:
*
cromoglicic acid
Cromoglicic acid (INN)—also referred to as cromolyn (USAN), cromoglycate (former BAN), or cromoglicate—is traditionally described as a mast cell stabilizer, and is commonly marketed as the sodium salt sodium cromoglicate or cromolyn sodium. ...
*
nedocromil
Nedocromil sodium is a medication considered a mast cell stabilizer which acts to prevent wheezing, shortness of breath, and other breathing problems caused by asthma. It is administered by an inhaler under the brand name Tilade, and as an eye dr ...
lodoxamide
Lodoxamide is an antiallergic pharmaceutical drug. It is marketed under the tradename Alomide in the UK. Like cromoglicic acid it acts as a mast cell stabilizer. In 2014 lodoxamide and bufrolin were found to be potent agonists at the G protein- ...
gold standard
A gold standard is a backed currency, monetary system in which the standard economics, economic unit of account is based on a fixed quantity of gold. The gold standard was the basis for the international monetary system from the 1870s to the ...
in the
biochemical
Biochemistry, or biological chemistry, is the study of chemical processes within and relating to living organisms. A sub-discipline of both chemistry and biology, biochemistry may be divided into three fields: structural biology, enzymology, ...
evaluation of novel synthetic GPR35 agonists, because it remains potent in an
animal model
An animal model (short for animal disease model) is a living, non-human, often genetic-engineered animal used during the research and investigation of human disease, for the purpose of better understanding the disease process without the risk of ha ...
. Most other known agonists display high selectivity towards the human GPR35
orthologue
Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a speci ...
. This phenomenon is well established for other GPCRs and complicates the development of
pharmaceutical drugs
Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the ...
.
Antagonists
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.inverse agonism. They are, however, highly species-selective, and practically inactive at the
rodent
Rodents (from Latin , 'to gnaw') are mammals of the Order (biology), order Rodentia ( ), which are characterized by a single pair of continuously growing incisors in each of the upper and Mandible, lower jaws. About 40% of all mammal specie ...
receptor orthologues.
Clinical significance
Deletion of the ''GPR35'' gene may be responsible for
brachydactyly mental retardation syndrome
Brachydactyly () is a medical term denoting the presence of abnormally short Digit (anatomy), digits (fingers or toes) at birth. The shortness is relative to the length of other long bones and other parts of the body. Brachydactyly is an inherite ...
oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.
in
stomach cancer
Stomach cancer, also known as gastric cancer, is a malignant tumor of the stomach. It is a cancer that develops in the Gastric mucosa, lining of the stomach. Most cases of stomach cancers are gastric carcinomas, which can be divided into a numb ...