The growth-hormone-releasing hormone receptor: signal transduction, gene expression, and physiological function in growth regulation.

We now summarize key issues that we have investigated and highlight additional areas that need to be addressed. We are interested in two basic aspects of the GHRH pathway, those occurring in the brain, involving the synthesis of GHRH, and those occurring in the pituitary, involving signaling by GHRH. We have a long-term interest in the activity and regulation of the hypothalamic neurosecretory cells that synthesize GHRH. With respect to human disease, it is interesting that, despite the primal role played by GHRH in growth-hormone secretion, no mutations in the GHRH gene have yet been identified in association with growth disorders. Focusing on the downstream signaling components of the GHRH pathway, we now know quite a lot about the structure of the GHRH receptor and about some aspects of the signal transduction pathways that mediate the actions of GHRH. With respect to human disease, we have found that in an animal model, the little mouse, a mutation of the GHRH receptor results in growth-hormone deficiency and a dwarf phenotype, and there are ongoing attempts in several laboratories to try to identify similar inactivating mutations in the GHRH receptor in patients with isolated growth-hormone deficiency. Conversely, there is also substantial interest in whether activating mutations in this receptor might be identified in patients with growth-hormone-secreting pituitary tumors. We are also interested in whether there are additional receptors that might mediate some of the extrapituitary actions of GHRH. Finally, a major direction we are taking in the laboratory at the present time is toward understanding the developmental, hormonal, and tissue-specific regulation of the GHRH receptor gene.