Neuronal cellular distribution

The nervous system contains an unusually diverse set of intermediate filaments (Table 8-2) with distinctive cellular distributions and developmental expression [21, 22]. Despite their molecular heterogeneity, all intermediate filaments appear as solid, rope-like fibers 8-12 nm in diameter. Neuronal intermediate filaments (NFs) can be hundreds of micrometers long and have characteristic sidearm projections, while filaments in glia or other nonneuronal cells are shorter and lack sidearms (Fig. 8-2). The existence of NFs was established long before much was known about their biochemistry or properties. As stable cytoskeletal structures, NFs were noted in early electron micrographs, and many traditional histological procedures that visualize neurons are based on a specific interaction of metal stains with NFs. 

Moore, D., Chambers, J., Waldvogel, H., Faull, R. and Emson, P. Regional and cellular distribution of the P2Y, purinergic receptor in the human brain striking neuronal localisation. J. Comp. Neurol. 421 374-384, 2000. 

In mammals there are four genes for the PMCA pump, two of which are expressed in all tissues (housekeeping enzymes), whereas the other two, which have a particularly high affinity for calmodulin, are restricted in their cellular distribution, notably to neurons. Additional variants of PMCAs are produced by alternative splicing of their primary RNA transcripts. 

Tholey G, Ledig M, Kopp P, et al. 1988. Levels and sub-cellular distribution of physiologically important metal ions in neuronal cells cultured from chick embryo cerebral cortex. Neurochem Res 13 1163-1167. 

The cellular distributions of the three and three a2 receptor subtypes still are incompletely understood. Recent findings indicate that a2 subtype junctions as a presynaptic autoreceptor in central noradrenergic neurons. 

Protein kinases differ in their cellular and subcellular distribution, substrate specificity and regulation. These properties determine the functional roles played by the very large number of protein kinases that have been found in mammalian tissues, most of which are known to be expressed in neurons [3]. The major classes of protein serine-threonine kinase in the brain, listed in Table 23-1, are covered in this chapter. The major classes of protein tyrosine kinases in the brain are discussed in Chapter 24. 

Some members of this family have been shown to mediate the dephosphorylation of MAPKs under physiological conditions. Others dephosphorylate Cdc-2 and related CDKs. However, relatively little is known to date about the regional distribution of these dual-functioning phosphatases in the brain and the specific function these enzymes serve in the regulation of neuronal signal transduction. Considerable interest has focused on one particular MAPK phosphatase, which can be induced very rapidly, at the level of gene transcription, in target cells in response to cellular activation [44]. 

The normal cellular form of prion protein (PrPc) can exist as a Cu-metalloprotein in vivo (492). This PrPc is a precursor of the pathogenic protease-resistant form PrPsc, which is thought to cause scrapie, bovine spongiform encephalopathy (BSE), and Creutzfeldt—Jakob disease. Two octa-repeats of PHGGGWGQ have been proposed as Cu(II) binding sites centered on histidine (493). They lack secondary and tertiary structure in the absence of Cu(II). Neurons may therefore have special mechanisms to regulate the distribution of copper. 

Inhaled nicotine is efficiently delivered to the brain (see chapter by Benowitz, this volume) where it selectively interacts with its central targets, the neuronal nicotinic acetylcholine receptors (nAChRs). The multiple subtypes of uAChR (see chapter by Collins et al, this volume) all bind nicotine but with different affinities, depending on the subunit composition of the uAChR. Binding may result in activation or desensitisation of uAChRs, reflecting the temporal characteristics of nicotine dehvery and local concentration of nicotine. Another level of complexity of the actions of nicotine reflects the widespread and non-uniform distribution of uAChR subtypes within the brain, such that nicotine can influence many centrally regulated functions in addition to the reward systems. In this chapter, we address the consequences of nicotine interactions with nAChRs at the molecular, cellular and anatomical levels. We critically evaluate experimental approaches, with respect to their relevance to human smoking, and contrast the acute and chronic effects of nicotine. 

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