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Synthetic and endogenous growth hormone secretagogues
The pituitary gland secrets several important hormones to regulate a variety of physiological functions in our body. Growth Hormone (GH) controls human growth and development, and is secreted by somatotropes. As we get older, a disturbance of GH secretion leads to a GH deficiency. This deficiency contributes to the degenerative changes that occur in the cardiovascular, muscle and central nervous systems of the elderly. GH deficiency also occurs in several disease states, such as AIDS, severe burns, heart failure, etc. In patients with GH deficiency, GH replacement yields beneficial and positive outcomes. However, the significant cost of producing protein GH and inconvenience of an intravenous injection of hormone limit its clinic uses. The injection of GH also hampers the endogenous GH releasing rhythm. Consequently, methods for increasing GH secretion without disturbing the body's own GH releasing pattern are actively sought by research scientists worldwide.
The major research interest of the Endocrine Cell Biology Group is to understand how GH is made and released by cells (somatotropes) in the pituitary gland underneath the brain. Several aspects of the cells are being investigated including 1) the cell membrane ion channels, 2) the signalling molecules that communicate from the outside environment to the inside of cells, 3) the synthesis of GH and receptors for GH-releasing hormone, synthetic GH-releasing secretagogues and GH releasing inhibitory hormone, and 4) cell hormone secreting machinery. The overall goal of our research in this area is to determine what processes within the pituitary somatotropes involved in GH synthesis and secretion, and to develop new and more effective therapeutic drugs to treat GH deficiency.
The release of GH from pituitary cells is mainly controlled by two hormones from the brain - a stimulating hormone, GH-releasing hormone (GHRH), and an inhibitory factor, somatotropin-releasing inhibitory factor (SRIF). A new regulatory system of small molecular GH secretagogues for GH release has recently become apparent, especially with the recent discovery of a possible endogenous GH secretagogue, or ghrelin. It is also clear that the sensitivity of pituitary cells to GH releasing and inhibitory factors can change in response to different environmental conditions. We are currently testing synthetic GH secretagogues (GHS) on cultured pituitary cells to see if GHS modifies the sensitivity of somatotropes to GHRH and SRIF. This has the potential to correct GH deficiency using synthetic GHS. We are also investigating the effect of GHS on the synthesis of receptors for GHRH and GHS itself. We measure the level of mRNA and protein for GHRH, GHS and SRIF receptors, and search for changes that may occur. It has been shown that low doses of GHS and GHRH treatment of somatotropes increased GHRH receptor and GH synthesis. The increase in GH and GHRH receptor leads to a priming effect of GHS and GHRH on somatotropes. We are now investigating the signalling systems involved in this priming effect and the possible difference between the different structure of GHS.
We have also been studying the movement of ions across the membrane of somatotropes. As K+ channels are vitally important for maintaining resting membrane potential and cell excitability, any change in K+ channels will alter cell sensitivity to GHRH, SRIF and GHS. Using a combination of techniques, ranging from patch clamp for ion channel recording, to intracellular dialysis of biologically active antibodies and peptides, we have been able to show a decrease in the K+ currents by GHS via a mediation of protein kinase A (PKA) system. Combined with our previous results, we believe that GHS actually influence somatotropes sensitivity to GHRH through both long and short term actions through two different signalling systems in somatotropes. Short term effect of GHS is mainly through cAMP/PKA system to change membrane K+ and Ca2+ conductance, and the long term effect is via the PKC system for the increase in membrane voltage-gated K+ conductance. We are now linking those two types of ionic conductance to the physiological function of the somatotropes. In the other hand, there are 5 subtypes of SRIF receptors in somatotropes. Using specific analogues of SRIF receptor subtypes, we have demonstrated that SRIF-receptor 2 and 4 were involved in the increase in K+ currents by SRIF. Mechanism for such change is under investigation. Subtypes involved in the Ca2+ current response to SRIF are also under investigation.
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