somatic integration of single ion channel responses of α7 nicotinic acetylcholine receptors enhanced by pnu-120596体细胞的集成单离子通道响应α7烟碱乙酰胆碱受体增强pnu - 120596.pdf

Somatic Integration of Single Ion Channel Responses of a7 Nicotinic Acetylcholine Receptors Enhanced by PNU- 120596 Victor V. Uteshev*¤ Department of Pharmacology , Southern Illinois University School of Medicine, Springfield, Illinois, United States of America Abstract Positive allosteric modulators of highly Ca2+-permeable a7 nicotinic acetylcholine receptors, such as PNU-120596, may become useful therapeutic tools supporting neuronal survival and function. However, despite promising results, the initial optimism has been tempered by the concerns for cytotoxicity. The same concentration of a given nicotinic agent can be neuroprotective, ineffective or neurotoxic due to differences in the expression of a7 receptors and susceptibility to Ca2+ influx among various subtypes of neurons. Resolution of these concerns may require an ability to reliably detect, evaluate and optimize the extent of a7 somatic ionic influx, a key determinant of the likelihood of neuronal survival and function. In the presence of PNU-120596 and physiological choline (,10 mM), the activity of individual a7 channels can be detected in whole-cell recordings as step-like current/voltage deviations. However, the extent of a7 somatic influx remains elusive because the activity of individual a7 channels may not be integrated across the entire soma, instead affecting only specific subdomains located in the channel vicinity. Such a compartmentalization may obstruct detection and integration of a7 currents, causing an underestimation of a7 activity. By contrast, if step-like a7 currents are integrated across the soma, then a reliable quantification of a7 influx in whole-cell recordings is possible and could provide a rational basis for optimization of conditions that support survival of a7-expressing neurons. This approach can be used to directly correlate a7 single-channel