A possible mechanism for neurofilament slowing down in myelinated axon: Phosphorylation-induced variation of NF kinetics.

Neurofilaments(NFs) are the most abundant intermediate filaments that make up the inner volume of axon, with possible phosphorylation on their side arms, and their slow axonal transport by molecular motors along microtubule tracks in a "stop-and-go" manner with rapid, intermittent and bidirectional motion. The kinetics of NFs and morphology of axon are dramatically different between myelinate internode and unmyelinated node of Ranvier. The NFs in the node transport as 7.6 times faster as in the internode, and the distribution of NFs population in the internode is 7.6 folds as much as in the node of Ranvier. We hypothesize that the phosphorylation of NFs could reduce the on-track rate and slow down their transport velocity in the internode. By modifying the '6-state' model with (a) an extra phosphorylation kinetics to each six state and (b) construction a new '8-state' model in which NFs at off-track can be phosphorylated and have smaller on-track rate, our model and simulation demonstrate that the phosphorylation-induced decrease of on-track rate could slow down the NFs average velocity and increase the axonal caliber. The degree of phosphorylation may indicate the extent of velocity reduction. The Continuity equation used in our paper predicts that the ratio of NFs population is inverse proportional to the ratios of average velocity of NFs between node of Ranvier and internode. We speculate that the myelination of axon could increase the level of phosphorylation of NF side arms, and decrease the possibility of NFs to get on-track of microtubules, therefore slow down their transport velocity. In summary, our work provides a potential mechanism for understanding the phosphorylation kinetics of NFs in regulating their transport and morphology of axon in myelinated axons, and the different kinetics of NFs between node and internode.

The cost of an action potential.

Neuronal modules, or 'cell-assemblies', comprising millions of mutually interconnected cells have been postulated to form the basis of many functions of the brain, such as mood, sleep, hunger, vigilance, and more. Depending on the extent of the module, neurocommunication in cell-assemblies might exceed metabolic resources. A medium-size (10000 neurons) module would require at least 10 J per l of brain, based on a calculated cost of an isolated action potential (AP) of 10(11)-10(12) molecules of ATP per cm(2) of cell membrane, with an absolute minimum of 10(6) ATP at a node of Ranvier. The figure matches the cost of depolarizing the unmyelinated axon of the large monopolar cell in the blowfly retina. A circuit model of the cell membrane, based on abrupt changes of Na(+) and K(+) conductances, is used to emulate the AP and to assess the resulting ionic unbalance. The cost of an AP is equated to the metabolic energy necessary to fuel ATP-based pumps that restore intracellular K(+). The high metabolic demand of a cell-assembly suggests that less expensive means of neurocommunication may be involved, such as non-synaptic diffusion neurotransmission (NDN), which would comply with a proposed law of conservation of space and energy in the brain.