Structure and Function of GHRH
This gene encodes a member of the glucagon family of proteins. The encoded preproprotein is produced in the hypothalamus and cleaved to generate the mature factor, known as somatoliberin, which acts to stimulate growth hormone release from the pituitary gland. Variant receptors for somatoliberin have been found in several types of tumors, and antagonists of these receptors can inhibit the growth of the tumors. Defects in GHRH are a cause of dwarfism, while hypersecretion of the encoded protein is a cause of gigantism. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed.
Gene Ontology (GO) annotations related to GHRH include hormone activity and growth hormone-releasing hormone receptor binding. An important paralog of this gene is ADCYAP1. Diseases associated with GHRH include Acromegaly and Gangliocytoma. Among its related pathways are Apoptotic Pathways in Synovial Fibroblasts and GPCR Pathway.
Three dimensional structures for GHRH Gene
Pathways
GHRH in Akt Signaling (Protein Kinase B Signaling):
The binding of GHRH to its receptor (GHRHR) can activate various downstream signaling pathways, one of which includes the PI3K/Akt pathway. Once GHRH binds to GHRHR, it can stimulate the activation of phosphatidylinositol 3-kinase (PI3K). Activated PI3K then phosphorylates and activates Akt, a crucial kinase in the cell survival pathway. Once activated, Akt can mediate various cellular responses, including cell survival, growth, and proliferation. It can inhibit pro-apoptotic proteins and promote cell survival mechanisms. Through the Akt signaling pathway, GHRH can thus influence growth, metabolism, and survival of cells.
GHRH in cAMP Pathway:
The primary signaling mechanism for GHRH after binding to its receptor is the activation of adenylate cyclase, which leads to the formation of cyclic AMP (cAMP). The increase in cAMP activates protein kinase A (PKA). PKA then translocates to the nucleus, where it can phosphorylate and activate cAMP response element-binding protein (CREB). Phosphorylated CREB can bind to the cAMP response elements (CRE) on the DNA, leading to the transcription of genes necessary for growth hormone (GH) release. In this way, GHRH regulates the synthesis and secretion of GH through the cAMP pathway.
GHRH in Cellular Apoptosis Pathway:
GHRH, through its anti-apoptotic effects, can play a role in cell survival. Its mechanism often intersects with the Akt signaling pathway, as mentioned above. Once GHRH activates the Akt pathway, Akt can inhibit the activity of several pro-apoptotic factors, such as Bad, Bax, and caspase-9. Furthermore, the activation of Akt can also lead to the transcription of genes that encode for anti-apoptotic proteins, further enhancing cell survival. Additionally, GHRH can reduce the levels of pro-apoptotic proteins like caspase-3, further emphasizing its role in inhibiting apoptosis and promoting cell survival.
Drugs
About GHRH, there are 47 pipelines under study, 40 of which have been approved.
Soybean oil is an oil used as a source of calories and essential fatty acids in selected patients for total parenteral nutrition (TPN) therapy and prevention of essential fatty acid deficiency.
Acipimox is a niacin derivative used in Fredrickson type IIb and type IV hyperlipoproteinemia.
Atropine is a muscarinic antagonist used to treat poisoning by muscarinic agents, including organophosphates and other drugs.
Bromocriptine is a dopamine D2 receptor agonist used for the treatment of galactorrhea due to hyperprolactinemia and other prolactin-related conditions, as well as in early Parkinsonian Syndrome.
Clonidine is an alpha-2 adrenergic agonist used to treat hypertension and severe cancer pain, among other conditions, and to treat withdrawal symptoms from various substances. It is also used to aid in the diagnosis of pheochromocytoma and to prevent migraines.
Deflazacort is a corticosteroid used to treat Duchenne muscular dystrophy.
Dopamine is a catecholamine neurotransmitter used to treat hemodynamic imbalances, poor perfusion of vital organs, low cardiac output, and hypotension.
Estradiol is an estrogenic steroid used to treat vasomotor symptoms of vulvar and vaginal atrophy in menopause, hypoestrogenism, prevention of postmenopausal osteoporosis, treatment of breast cancer, and advanced androgen-dependent carcinoma of the prostate.
Fenfluramine is fenfluramine is a phenethylamine that is structurally similar to serotonin. Due to its ability to increase extracellular serotonin levels, modulate serotonergic and other neurologic receptors, and control neurotransmission, it is effective in treating pharmacoresistant seizures.
Lanreotide is a somatostatin analog used for the treatment of unresectable, well- or moderately-differentiated, locally advanced or metastatic gastroenteropancreatic neuroendocrine tumors and acromegaly.
Levodopa is a dopamine precursor used in the management of Parkinson's disease, often in combination with carbidopa, as well as other conditions associated with parkinsonism.
