Environmental Factor, July 2007, National Institute of Environmental Health Sciences
PI Outlines Upcoming Developments in Nicotinic Receptor Research
By Eddy Ball
Neurobiologist Jerrel Yakel, Ph.D., used the occasion of his upcoming Board of Scientific Counselors' review as the platform for a lecture on June 6 in Rall F-193. Speaking on "Nicotinic Receptor Channel: Structure, Function and Possible Roles in Neurological Disorders and Disease," Yakel, who is a senior investigator in the Laboratory of Neurobiology at NIEHS, surveyed his recent work in the field and described the direction his group's work will take in the next year and beyond.
Using electrophysiology, iontophoresis and fluorescence imaging techniques, Yakel's lab has studied activation of neuronal nicotinic acetylcholine receptors (nAChRs) in the hippocampal and cortical sections of the brains of mammals and the receptors' induction of calcium (Ca2+) signals. He and his colleagues have mimicked synapses in brain slices to evaluate rates of activation, desensitization and Ca2+ permeability of receptors.
Situated in the soma and, to a lesser extent, in the dendrites of neurons, nAChRs are ligand-gated ion-channel receptors that mediate fast excitory synaptic transmission in the central and peripheral nervous system. Receptor regulation of calcium has been linked to a variety of functions in the brain related to synaptic transmission. How effectively these receptors mediate rapid electrical impulses in the nervous system can impact the development of neurons, learning and memory formation, and reward mechanisms, such as pleasure and satiation.
Along with their role in helping to maintain nicotine addiction through reward reinforcement, hence the designation "nicotinic," these receptors are a potential therapeutic target in several disease conditions of wide concern to the medical and research community:
- Alzheimer's Disease - dementia may be associated with deficits in cholinergic synaptic transmission
- Parkinson's Disease - epidemiological and recent in vivo animal research suggest nicotine may have a protective effect
- Epilepsy and neuromuscular diseases - the excitotoxic effects of a rapid influx of calcium into neuronal cells in the brain may exacerbate the conditions
- Schizophrenia - the high incidence of heavy smoking among patients could be a form of self-medication
- Pain - manipulation of nAChRs may enhance the effects of analgesic compounds that work through these receptors
Thus far, scientists have identified 11 subunits of nAChRs that affect synaptic transmission in different sections of the brain. Receptor subunits are designated by combinations of a Greek alphabetical character and an Arabic numeral, such as α7 and ß4 (see graphic on "Distribution and possible roles of nAChRs").
"nAChRs," Yakel wrote in his most recent study, "have the capacity to elicit changes in cytoplasmic calcium ([Ca2+]i) levels, which has implications for regulating various signal transduction cascades, synaptic plasticity, and memory processes." Consequently, understanding the mechanisms by which the subunits of nAChRs influence calcium can help researchers identify their effects on epigenetic alterations related to the development of neurodegenerative disorders.
Yakel also gave the audience a preview of his most recent study, a collaboration with former LN Research Fellow Dmitriy Fayuk, Ph.D., that is still in press. This research reports for the first time the spatial and temporal properties of the [Ca2+]i signals and currents stimulated by the rapid activation of α7-containing nAChRs in the dendrites of interneurons in hippocampal slices and cultured hippocampal neurons. To evaluate properties of these signals and currents, the researchers measured signaling distance in microns and duration in milliseconds.
As impressive as the advances in this research have been, Yakel readily admits that there are many questions still to be answered. "[For example,] we still don't exactly know the synaptic aspect of these receptors," he conceded. "We're trying very hard to figure it out and garner the tools to do that."
Future directions for Yakel and his colleagues in the LN Ion Channel Physiology Group involve exploring receptor activation in other areas of the brain, including the amygdala, the region suspected of involvement in fear and aversively motivated memory, and the basal ganglia, with its implications in dopamine synthesis and Parkinson's Disease. When he takes the podium in his presentation to the Board of Scientific Counselors reviewing the work in his lab, Yakel will offer three future directions for their consideration:
- Tracing cholinergic synapse development (co-cultures) and the regulation of synaptic signaling
- Tagging receptors with green fluorescent proteins and quantum dots, a cutting-edge nanotechnology used in pharmacokinetics studies, to evaluate mobility in membranes and cycling patterns
- Delineating the role of nAChRs in inflammation, glial cell damage and phosphorylation of a protein family known as MARCKS (myristoylated alanine-rich C-kinase substrate)