Category Archives: Modeling

Distribution of voltage-gated Na+ channels throughout dendrites and axon

There are three primary voltage-gated Na+ channel subunits expressed in adult brains: Nav1.1, Nav1.2, and Nav1.6 (Nav1.5 seems to only be in cardiac/etc cells, and the rest are only expressed during development). Each of these channel types has different activation kinetics and thresholds, possibly allowing each of them to perform distinct functions in a single cell. Since channels are not homogeneously distributed throughout cells, but rather distributed in specific fashions, understanding Na+ channel localization is important to understanding function at the signal neuron level.

Hu et al. investigated the distribution of Nav1.2 and Nav1.6 channels in axon in the context of action potential initiation and propagation. It is has been known for a while that action potentials are not initiated at the soma, but rather proximally on the axon at the axon initial segment (AIS). Using immunostaining in layer 5 pyramidal neurons of rat prefrontal cortex, they find peak immunoreactivity ~20 um from the soma, with voltage-clamp recordings confirming peak Na+ current decreases with distance from the soma. Importantly, immunostaining showed a peak for Nav1.2 between 5 to 15 um from the soma and a peak for Nav1.6 between 30 and 50 um from the soma.

When they examined the voltage dependence of activation showed a half-activation of -29.7 mV at the soma and -43.9 mV at the axon, with no difference in slope. Half-inactivation showed a similar shift. This means that somatic Na+ channels are harder to activate, though less inactivated at steady state. Using this data for a computational model of the axon, they attempted to determine what the role of each channel was. Threshold changes are primarily due to Nav1.6 density, with less effect seen from Nav1.2 density. However, Nav1.2 density seems to control action potential backpropagation failure rate – removal or reduction of Nav1.2 leads to a hyperpolarized failure threshold. That is, distal Nav1.6 is primarily involved in generating action potentials, and Nav1.2 is responsible for spreading it into the somatodendritic compartments. I’d be curious to know what computational role the lower distal threshold of AP initiation plays.

More recently, Lorincz and Nusser investigated the identity of Nav channels in the soma. Conventional immunofluorescence techniques are not sensitive enough to detect Nav subunits in dendrites. For a technical reason I do not fully understand, a low pH approach managed to increase the strength of reactions. Even though it is quite noisy, they managed to get a decent snapshot of channel density. In CA1 pyramidal cells, they confirmed that Nav1.6 appears to show a gradient increase distally from the soma. They could not detect Nav1.2 immunoreactivity in soma or dendrites – though they could in AIS – and could only find Nav1.1 in axonlike processes and AISs of GABAergic interneurons. This appears different from Hu et al’s somatic data in layer 5, where they did find Nav1.2. Nav1.6, however, was found in somata and dendritic compartments. Comparing Nav1.6 at the same distance from the soma, oblique dendrites contain less Nav1.6 than the main apical dendrites. The data looks noisy so I’d be careful about overinterpreting that for now, however.

References
Hu W, Tian C, Li T, Yang M, Hou H, Shu Y. (2009). Distinct contributions of Nav1.6 and Nav1.2 in action potential backpropagation. Nature Neuroscience 12 (8): 996-1002. DOI: 10.1038/nn.2359

Lorincz A, Nusser Z. (2010). Molecular identity of dendritic voltage-gated sodium channels. Science 328: 906-909. DOI: 10.1126/science.1187958

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Filed under Ion channels, Modeling