Detailed Description

Signaling pathways modulate the function of neurons and neuronal networks through diverse processes. The most well-known function of signaling pathways is synaptic plasticity, which controls neuronal networks via modulation of the strength of synaptic connections. Signaling pathways also are critical for neuronal development, axon guidance, and regulation of transcription and translation. Signaling pathways are activated by the G protein-coupled transmembrane receptors, such as metabotropic glutamate receptors or noradrenergic receptors; by the receptor tyrosine kinases; and by calcium influx through NMDA receptors or voltage-dependent calcium channels.

Calcium

Due to the importance of calcium, its concentration is tightly regulated by buffers and pumps. One of these calcium buffers, known as calmodulin, is not inert; rather, it can activate diverse enzymes such as adenylyl cyclase, calcineurin, phosphodiesterase type 1B, and calcium-calmodulin-dependent protein kinase II. In addition to calcium influx through plasma membrane channels, both the mitochondria and the smooth endoplasmic reticulum (SER) are sources of calcium. Two types of calcium permeable channels reside on the SER: the inositol trisphosphate receptor channel and the ryanodine receptor channel. Calcium-dependent calcium release through these channels can lead to oscillations or waves of calcium, depending on various factors.

Kinases

The second messengers activated through transmembrane receptors have multiple downstream targets, including ionic channels, kinases, and phosphatases. Of the thousands of kinases and phosphatases in the proteome, several have a demonstrated role in synaptic plasticity, though their relative importance depends on the brain region and cell type. Protein kinase type C is a calcium- and lipid-activated kinase which is critical for LTP in the cerebellum. Protein kinase type A is a cAMP-activated kinase, which is critical for LTP in the striatum, and for several long-lasting forms of LTP in the hippocampus. Gene transcription and protein translation are required for both memory and for long-lasting forms of synaptic plasticity. One kinase that appears to bridge these other kinases and transcription is the ERK1/2 forms of MAPK (mitogen-activated protein kinase).

Modeling Techniques

Calcium dynamics and signaling pathways are modeled as cascades of biochemical reactions, both bimolecular reactions and enzyme reactions, and diffusion. Many special purpose simulators are available to implement these signaling pathways, either using stochastic techniques or deterministic approaches. Modeling calcium influx requires the simulator to have capabilities for modeling membrane potential. Due to the diversity in temporal and spatial scale involved in modeling neuronal electrical activity coupled to reaction-diffusion pathways, very few models incorporate signaling pathways in entire neurons, though the number of such models is increasing as computational power increases.

Cross-References