Goy Lab - Research

Biochemical Processing of Information at the Cellular Level

Figure 1.

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.

Figure 2.

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.

One particularly interesting aspect of this work involves the peptide uroguanylin, which is found both in the intestine and in the kidney (see figure 2). 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.

Figure 3.

In parallel with our mammalian studies, we have recently turned to a simple invertebrate model system (the crustacean heart) in order to begin a detailed investigation into the roles of cyclic GMP-based signaling in cardiac function. The crustacean heartbeat is controlled by a small ganglion, comprised of nine neurons, that lies within the lumen of the heart and spontaneously produces regular bursts of action potentials that drive rhythmic contractions of the heart muscle (figure 3). Our preliminary studies show that the output of the cardiac ganglion is profoundly suppressed by NO. In addition, we have found that crustacean heart muscle is itself an unexpectedly rich source of NO, containing among the highest levels of nitric oxide synthase (NOS) detectable in the animal. Interestingly, the cardiac form of NOS is strongly activated by calcium ions, which implies that an active heart will generate NO in direct proportion to the rate and strength of the heartbeat (which is driven, like all muscle contractions, by oscillations in cytoplasmic calcium levels). Thus we believe that NO acts as an intracardiac messenger, relaying feedback information from the heart muscle to the ganglion. We are currently trying to understand how this feedback pathway helps to optimize cardiac performance.

Michael Goy is a member of the Curriculum in Neurobiology and an acoustically correct Triangle-area guitarist.