Paul A. St. John
Associate Professor of Cell Biology and Anatomy
Ph. D., Harvard University
Teaching Areas- Medical Histology & Cell Biology; Graduate Cellular and Molecular Neurobiology
E-mail: stjohn@u.arizona.edu
Research Interest:
Cell biology and developmental regulation of neurotransmitter receptors
Neuronal differentiation, synapse formation, and synaptic plasticity all require neurons and their target cells to express the right receptors for neurotransmitters and to target those receptors dynamically to the right part(s) of the cell. Abnormalities in receptor expression or localization can cause congenital defects, neurological and psychiatric diseases, and death. In addition, neurotransmitter receptors are the biological targets of a host of drugs that drive addictive behaviors. One goal of our research is to understand cellular and molecular mechanisms that govern receptor expression and localization. Another is to understand how certain addictive drugs interfere with normal receptor expression and localization.
Well, how is receptor expression controlled in developing neurons? And how are receptors targeted on the surfaces of cells? And why is nicotine addictive? We are addressing these questions by examining two groups of receptors, the glycine receptors and the nicotinic class of acetylcholine receptors.
In studies of glycine receptors (GlyRs), we and others have found that neurons change their expression of GlyR subunits during development, and that the subcellular distribution of GlyRs is developmentally regulated, as well. These changes allow GlyRs apparently to mold the differentiation of young neurons, but then to mediate rapid synaptic transmission between mature neurons. Changes in GlyR expression involve both the differential expression of multiple receptor-subunit genes and the regulation of splicing of subunit pre-mRNAs. They can be observed through the molecular analysis of transcripts for receptor subunits, the microscopic analysis of the distribution of GlyRs on the cells that express them, and the physiological analysis of responses to glycine in developing neurons. Because key aspects of the developmental regulation of GlyR expression occur in neurons grown in culture, we can examine the role that neuronal activity and/or intercellular interactions play in that regulation.
Much is known about the molecular structure and function of nicotinic acetylcholine receptors (nAChRs), but little is known about their trafficking within cells. We have found that agonists including the tobacco alkaloid nicotine can cause endocytosis of cell-surface nAChRs that can reach dramatic levels: more than half of a cell's nAChRs can be internalized from its surface during an agonist exposure of just a few hours. We are examining both the basic cellular/molecular mechanisms of this agonist-induced endocytosis and the extent to which different subtypes of nAChRs are subject to this kind of regulation. Our goal is to understand both the possible contribution of regulated endocytosis of nAChRs to normal synaptic plasticity and its possible involvement in nicotine addiction.
Selected Publications:
St. John PA, Gordon H (2001) Agonists cause endocytosis of nicotinic acetylcholine receptors on cultured myotubes. J Neurobiol 49:212-223.
Withers MD, St. John PA (1997) Embryonic rat spinal cord neurons change expression of glycine receptor subtypes during development in vitro. J Neurobiol 32:579-592.
Kumar DV, Nighorn A, St. John PA. Role of Nova-1 in regulating a2N, a novel glycine splice variant, in developing spinal cord neurons. Pending.
