Gap Junctions And Neuropathology

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At least 15 connexin genes have been identified in the mammals. These genes are spread over five or six chromosomes: human 1, 6, 13, 15 and X; mouse 3, 4, 10, 11, 14 and X. Although they are so widespread, the genes (with the exception of that for Cx36) have a common structure: a single intron separating a small non-coding exon from a much larger exon which encodes the whole connexin sequence. Mutations of these genes have been implicated in a number of neuropathologies.

7.10.1 Deafness

Although over a hundred different forms of genetic deafness are known, well over half are due to a G)A substitution at codon 70 (G70A) in the CBJ2 gene coding for connexin 26 (Cx26) (chromosome 13 (13p11-12)). This leads to a premature 'stop' codon and a defective connexin protein being expressed in the stria vascularis, basement membrane, limbus and spiral prominence of the cochlea (see Figure 13.25). It is believed that a defective Cx26 prevents the proper recycling of K+ from synapses at the bases of the hair cells back into the K+-rich endolymph via the stria vascularis This disrupts the physiology of the organ of Corti and thus causes deafness. We shall see, in Chapter 11, that mutation of a gene encoding a K+ channel (MinK) has a similar effect. It has been suggested that the prevalence of a mutated Cx26 gene in the population is due to marriage of similarly challenged men and women.

7.10.2 Cataract

As with deafness there are many genetic causes of cataract. One cause, however, is a mutation in the connexin 50 (Cx50) gene on chromosome 1. A transition at nucleotide 262 leads to C being replaced by T (C262T) and this, in turn, causes proline88 to be replaced by serine (P88S). A second cause of cataract is an A to G transition at position 188 (A188G) in the connexin 46 (Cx46) gene on chromosome 13. This leads to the substitution of serine for asparagine at position 63 in the Cx46 protein (N63S). Yet another cause is a frameshift mutation at nucleotide 1137 in the Cx46 gene. This causes a mistranslation of 56 C-terminal amino acids in the Cx46 protein. All of these mishaps cause defective gap junctions between lens fibres and thus to patchy, dust-like, lens opacities known as pulverulant cataract.

7.10.3 Charcot-Marie-Tooth (type 2) disease

This is a rare X-linked disease. Whereas the more common type 1 CMT is caused by mutations affecting the genes coding for myelin proteins (especially P0) (see Section 7.7), the much rarer type 2 CMT is caused by mutation of the connexin gene, GJB1, encoding connexin 32 (Cx32), on the X chromosome (Xq13.1). Numerous amino acid substitutions have been detected as well as frame-shift and premature 'stop' codons. It has been found that the majority of these mutations occur in the connexin domain lining the pore or in the domain which forms the surface of attachment with the neighbouring connexin subunit in the adjacent membrane. Type 2 CMT involves loss of neurons in the anterior horn of the grey matter and in the posterior root ganglia, especially in the lumbar and sacral regions.

Both types of CMT disease are peripheral neuropathies. Whilst it is not surprising that type 1, affecting P0, is confined to the periphery, it is somewhat surprising that type 2 is similarly restricted, for connexin 32 figures prominently in oligodendroglia. It is possible that in the CNS other connexin genes can substitute for defects in con-nexin 32.

How does defective connexin 32 cause type 2 CMT disease? It has been shown that Schwann cells express Cx32 and concentrate it in the uncompacted myelin membranes adjacent to the nodes of Ranvier (paranodal region; see Figure 14.14) and in the incisures of Schmidt-Lanterman. In these regions gap junctions allow communication between the cytoplasm of the Schwann cell body and the cytoplasmic collar of the myelin sheath which wraps around the axon adjacent to the node of Ranvier. Derangement of these channels of communication could have disastrous effects on the well-being of the Schwann cell, its myelin and the enwrapped axon.

7.10.4 Spreading Hyperexcitability (Epilepsy) and Hypoexcitability (Spreading Depression)

Because they function as communication channels between cells, gap junctions have been suspected of being involved in spreading hyperexcitability (epilepsy) and spreading hypoexcitability (spreading depression). It has been shown that epileptic foci show enhanced expression of connexin 43 when compared with normal controls. Connexin 43 forms the basis of gap junctions between astroglia. Uncoupling gap junctions with agents such as halothane blocks the spread of hyperexcitability in experimental preparations.

Vice versa the rate of spread of hypoexcitability (spreading depression) induced by the focal application of K+ or glutamate is similar to the diffusion rate of Ca2+ through glial cell populations (2050 mm/s). Spreading depression (SD) is characterised by changes in electrical impedance, lengthening of refractory periods, increases in concentration of extracellular K+ ([K+]o) and variation in tissue volume. It has been detected in hippocampus, olfactory bulb, spinal cord, superior colliculus and cerebellum. SD may underlie several nervous diseases: seizure discharges, migraine, cerebral ischaemia.

Knockout techniques have created mice lacking connexins 32 and 43. These and other molecular biological techniques will undoubtedly throw much new light on the role of gap junctions in health and disease in the next few years.

Table 7.3 Classification of membrane receptors

Metabotropic lonotropic

DA-Rs NE-Rs mACh-Rs mGlu-Rs




Opioid Rs

Peptide Rs

NK-Rs iACh-Rs GABAA-R Gly-Rs iGluR-s

5-HT3-R P2TX-Rs

ACh = acetylcholine; CB=cannabinoid; DA=dopamine; GABA=g-aminobutyric acid; Glu=glutamate; Gly=glycine; 5-HT=5-hydroxytryptamine (serotonin); NE = norepinephrine (noradrenaline); NK=neurokinin; P=purine. The table only shows those receptors described in detail in succeeding chapters. There are many others, falling into one category or the other (especially the metabotropic category), which will be mentioned in passing.

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