Biochemical Processing of Information at the Cellular Level
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Research in my laboratory is concerned with biological signal transduction, the process by which extracellular signals (such as hormones and neurotransmitters) trigger changes in intracellular chemistry, and ultimately changes in cell physiology. Though this process is still somewhat mysterious, we do know that it typically depends on the regulated production of low-molecular-weight metabolites, known as second messengers. Inside the cell, second messengers initiate biochemical cascades that dictate the physiological state of enzymes, contractile proteins, and ion channels.
We are currently studying the properties of signaling cascades that employ the second messenger cyclic GMP. As shown in figure 1, two different guanylate cyclase families control the synthesis of cyclic GMP. Receptor-guanylate cyclase (rGC) family members are regulated by peptide hormones, which stimulate enzyme activity by binding to an extracellular ligand-binding domain. Soluble guanylate cyclase (sGC) family members are regulated by nitric oxide (NO), which stimulates enzyme activity by interacting with covalently attached heme groups.
Much of the focus of the lab over the last ten years has been on understanding the physiological functions of peptides that target mammalian rGCs. These peptides fall into two families: the natriuretic peptides (ANP, BNP, and CNP) and the guanylin-related peptides (guanylin and uroguanylin). Both peptide families play crucial roles in the regulation of blood pressure, through actions on ion transport and fluid movement in the gut and kidney, effects on calcium metabolism and contractile state of vascular smooth muscle, and effects on the rate and strength of the heartbeat. Abnormal changes in the cGMP levels of cells that are targeted by these peptides result in serious medical problems, such as chronic hypertension or life-threatening diarrhea.
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One particularly interesting aspect of this work involves the peptide uroguanylin, which is found both in the intestine and in the kidney (see figures 2 and 3). Current hypotheses suggest that this peptide may serve as a "shuttle diplomat" carrying information between the two tissues, and helping to ensure that salt intake (carried out by the intestine) is balanced by salt excretion (carried out by the kidney). This sort of fine tuning may be an important factor in helping the body to maintain a stable blood pressure in the face of fluctuating levels of dietary salt intake. Indeed, intravascular infusion of uroguanylin (like intravascular infusion of ANP) causes a marked increase in urinary sodium excretion by the kidney (figure 4). Although the effects of uroguanylin are slower than those of ANP, they last much longer, resulting over time in a profound natriuresis.
Michael Goy is a member of the Curriculum in Neurobiology and an acoustically correct Triangle-area guitarist.