GHRH stimulates GH production and release by binding to the GHRH receptor (GHRHR) on cells in the anterior pituitary.
Receptor The GHRHR is a member of the
secretin family of
G protein-coupled receptors, and is located on
chromosome 7 in humans. This protein is transmembranous with seven folds, and its molecular weight is approximately 44
kD. but also by the
phospholipase C pathway (IP3/DAG pathway), and other minor pathways. The
cAMP-dependent pathway is initiated by the binding of GHRH to its receptor, causing receptor conformation that activates
Gs alpha subunit of the closely associated G-Protein complex on the intracellular side. This results in stimulation of membrane-bound
adenylyl cyclase and increased intracellular
cyclic adenosine monophosphate (cAMP). cAMP binds to and activates the regulatory subunits of
protein kinase A (PKA), allowing the free catalytic subunits to translocate to the nucleus and phosphorylate the transcription factor
cAMP response element-binding protein (CREB). Phosphorylated CREB, together with its coactivators,
p300 and
CREB-binding protein (CBP) enhances the transcription of GH by binding to CREs
cAMP-response elements in the
promoter region of the GH gene. It also increases transcription of the GHRHR gene, providing
positive feedback. In the
phospholipase C pathway, GHRH stimulates phospholipase C (PLC) through the
βγ-complex of
heterotrimeric G-proteins. PLC activation produces both
diacylglycerol (DAG) and
inositol triphosphate (IP3), the latter leading to release of intracellular Ca2+ from the
endoplasmic reticulum, increasing cytosolic Ca2+ concentration, resulting in
vesicle fusion and release of secretory vesicles containing premade growth hormone. Some Ca2+ influx is also a direct action of cAMP, which is distinct from the usual
cAMP-dependent pathway of activating
protein kinase A. Activation of GHRHRs by GHRH also conveys opening of
Na+ channels by
phosphatidylinositol 4,5-bisphosphate, causing cell depolarization. The resultant change in the intracellular voltage opens a
voltage-dependent calcium channel, resulting in
vesicle fusion and release of GH. == Relationship of GHRH and somatostatin ==