The physiological role of ABCC5 (MRP5) in the regulation of hormone secretion from gut endocrine cells.

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As modern humans, we have a complicated relationship with food and few among us would view food simply as an energy source. The preparation and consumption of food plays a central role in our daily lives and many of us can remember in great detail the tastes, smells and textures of our favourite childhood dishes. Furthermore, our brains have evolved to reward us for eating calorie-dense food because until very recently, starvation was a very real threat. However, currently we find ourselves surrounded by sugary, fatty foods 24/7, and in deep trouble.Anyone who has ever been on a diet knows intuitively that appetite regulation is far more complex than a simple see-saw between feeling full and feeling hungry. A multitude of physiological signals regulate appetite and metabolism. Feelings of hunger is initiated by a shrunken, empty stomach through the vagus nerve, and the simultaneous secretion of the 'hunger hormone', ghrelin. These signals act on the brain to stimulate feelings of hunger. Feelings of satiety are signalled to the brain shortly after food arrives in the stomach; a distended stomach and a sharp drop in ghrelin levels mute hunger signals to the brain and the arrival of digested food in the small intestine engages a large array of hormone secreting cells, known as enteroendocrine cells. Hormones secreted from enteroendocrine cells regulate the secretion of digestive enzymes from the gall bladder and pancreas, the rate of movement of food through the gut, the secretion of insulin from the pancreas and feelings of satiety in the brain. Gut hormones therefore have many down-stream targets and act on the vagus nerve which innervate the gut, the brain, the distant hormone-secreting cells of the pancreas, and also on their enteroendocrine neighbours. This constant chit-chat between the hormone secreting cells of the gut and their targets is the focus of my research. Digested food is detected by receptors expressed on the membranes of enteroedocrine cells. Activation of these receptors trigger a cascade of events that culminates in the secretion of hormones from endetroendocrine cells, a process called exocytosis. Conversely, there should also be a brake in place, to turn exocytosis off once adequate hormone had been released. The detection of nutrients in the gut have been well studied, but we currently know little about the sequence of events which terminate hormone release and the communication taking place at the junctions where enteroendocrine cells and nerve endings colocalize. Specifically, my research investigates the role of a membrane transporter, ABCC5, which has been shown to transport neurotransmitters across cell membranes. This protein appears to play a central role in turning exocytosis signals off. When ABCC5 protein levels is artificially boosted by recombinant overexpression in a model cell line, hormone release is inhibited. When ABCC5 protein levels are knocked out, exocytosis is enhanced. In addition, an ABCC5 substrate, a neurotransmitter called NAAG, also inhibits exocytosis. Taken together, this would suggest that ABCC5 and molecules it transports across the enteroendocrine cell membrane is involved in switching exocytosis off.Our research investigates the role of enteroendocrine cells from two angles. First, we aim to identify the receptors and enzymes involved in the signalling cascades which regulate and terminate hormone exocytosis. Secondly, we take a wider whole-systems look and investigate the metabolic implications for knock-out mice, which lack ABCC5. If our hypothesis holds true, mice lacking ABCC5 will secrete more hormone in response to the arrival of digested food in the small intestine, will have a more robust insulin response and will display a 'lean phenotype'. Our research will help us understand the whole body impact of gut hormones and will help scientist from several different areas to make connections between systems previously studied in isolation.