Rae Nishi, professor of anatomy and neurobiology at the University of Vermont College of Medicine, described her ongoing research on nicotine’s role in promoting cell death during avian development, as well as its puzzling connection to cancer in a keynote seminar at Dartmouth-Hitchcock Medical Center on Wednesday.

While observing the growth of chicken embryos, Rae’s team recorded a peculiar peak of cell death in developing ganglia from postnatal day 8 to 14. Furthermore, they found that antagonists of the alpha-7 subunit of nicotine acetylcholine receptors (nAChR), receptors that mediate fast transmission at neuromuscular junctions and on ganglia, prevent the high level of cell loss observed during that period.

Naturally, alpha-7 nAChR came into detailed inspection. Rae’s team observed that a high level of alpha-7 nAChR corresponded to an increase in intercellular concentration of the Ca2+ ion. Furthermore, after nicotinic stimulation, some postnatal day 8 neurons exhibited a slower rate of Ca2+ decay, contributing to an overall increase in Ca2+ concentration within the cell. It is thought that the Ca2+ influx exceeded the threshold for cell survival and thus caused programmed cell death. 

“The primary goal was to determine if nicotinic signaling induced cell death and what molecules modulate this,” Rae said.

Rae recalled her initial shock in finding that one of the modulator molecules her team sought is in fact a chicken ortholog of prostate stem cell antigen (chPSCA). The antigen is a compound commonly found in high levels in prostate cancer and neuroblastoma.

“The implications of chPSCA are great,” Rae said.

chPSCA was one of the six recently discovered chicken genes that encode membrane-bound molecules, which fold into structures homologous to alpha-bungarotoxin, a molecule that blocks the activation of alpha-7 nAChR and blocks the increase of Ca2+ concentration, preventing cell death.

chPSCA, besides its implications for prostate cancer, is found to prevent choroid ganglia cell death.

“We are still wondering about why only choroids ganglia and not also cilliary ganglia,” Rae said. “More to research.”

Besides chPSCA as a potential modulator of alpha-7 nAChR, the cells themselves autonomously activate GPI-linked alpha-bungarotoxin that blocks alpha-7 nAChR activation and thereby prevents cell death. GPI is the abbreviation for glycosylphosphatidylinositol, a glycolipid attached to the C-terminus of a protein during posttranslational modification.

Cell death during avian embryo development can be prevented with chPSCA or the cells themselves acting autonomously. But what about the other five chicken genes discovered that could influence cell death? And what does it mean to have chPSCA as a probable modulator of alpha-7 nAChR?  What is nicotine’s significance for cancer?

These are questions to answer in the future, but for now Rae “feels good about where this is going.”