%0 Journal Article
%T Somatic Integration of Single Ion Channel Responses of ¦Á7 Nicotinic Acetylcholine Receptors Enhanced by PNU-120596
%A Victor V. Uteshev
%J PLOS ONE
%D 2012
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0032951
%X Positive allosteric modulators of highly Ca2+-permeable ¦Á7 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 ¦Á7 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 ¦Á7 somatic ionic influx, a key determinant of the likelihood of neuronal survival and function. In the presence of PNU-120596 and physiological choline (~10 ¦ÌM), the activity of individual ¦Á7 channels can be detected in whole-cell recordings as step-like current/voltage deviations. However, the extent of ¦Á7 somatic influx remains elusive because the activity of individual ¦Á7 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 ¦Á7 currents, causing an underestimation of ¦Á7 activity. By contrast, if step-like ¦Á7 currents are integrated across the soma, then a reliable quantification of ¦Á7 influx in whole-cell recordings is possible and could provide a rational basis for optimization of conditions that support survival of ¦Á7-expressing neurons. This approach can be used to directly correlate ¦Á7 single-channel activity to neuronal function. In this study, somatic dual-patch recordings were conducted using large hypothalamic and hippocampal neurons in acute coronal rat brain slices. The results demonstrate that the membrane electrotonic properties do not impede somatic signaling, allowing reliable estimates of somatic ionic and Ca2+ influx through ¦Á7 channels, while the somatic space-clamp error is minimal (~0.01 mV/¦Ìm). These research efforts could benefit optimization of potential ¦Á7-PAM-based therapies.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0032951