Trends in Cell Biology
ReviewsDiverse functions of vertebrate gap junctions
Section snippets
Channel structure
Cryoelectron microscopy and image analysis of highly ordered, two-dimensional crystals of C-terminally truncated connexin 43 (Cx43) were used to generate an electron-density map in projection at 7 Å resolution[30]. The density map reveals for each channel an inner ring of six transmembrane α helices lining the pore and a second outer ring of six α helices facing the membrane lipid. The inner and outer rings of α helices result from the precise alignment of helices in each of the apposed
Insights into gap junction functions of Cx32 in human disease and knockout (KO) mice
New information about the physiological functions of intercellular channels has emerged recently from studies of human mutations and connexin knockouts in mice. The X-linked form of Charcot–Marie–Tooth disease (CMTX), a neuropathy resulting in progressive degeneration of peripheral nerves, results from at least 90 different Cx32 mutations32, 33. Some of these mutations are inactivating[34], whereas other mutations result in altered channel activity[35]. Cx32 has been localized to the incisures
Human disease resulting from Cx26 mutations and the phenotype of the Cx26 KO mouse
Mutations in Cx26 are responsible for both autosomal recessive and dominant nonsyndromic deafness, characterized by hearing loss with no other organ systems affected[44]. The role of Cx26 loss in the pathophysiology of deafness is not known, but Cx26 is found at high levels within the cochlea of the inner ear, between supporting cells of the organ of Corti and in the spiral lamina facing the endolymphatic duct[45]. It is possible that serially arranged gap junctions of epithelial and connective
Female infertility in Cx37 KO mice
Homozygous Cx37 KO females are infertile because their developing ovarian follicles fail to advance past early antral stages[47]. Because of the lack of a gap-junction-mediated signal, most oocytes fail both to complete growth and to acquire meiotic competence. Immunohistochemistry has shown that Cx37 forms an essential component of the gap junctions formed between the oocyte and the granulosa cells of the cumulus[47](Fig. 2). The loss of Cx37 does not seem to qualitatively change the large
Abnormal cardiac conduction in mice lacking Cx40
Cx40 KO mice have indicated an important role for this connexin in the rapid conduction of impulses in the His–Purkinje system, a discrete pathway containing fast-conducting cells (Purkinje fibres) that coordinate the spread of excitation from the atrioventricular node to the ventricular myocardium49, 50(Fig. 3a). After a heartbeat is initiated in the pacemaker cells of the sinoatrial node located in the right atrium, depolarization spreads throughout the atrial myocardium, producing the P wave
Aberrant cardiac development in Cx43 KO mice
Cx43 is highly expressed in myocardium but is also found in many other cell types[53]. Disruption of the gene encoding Cx43 resulted in animals with a malformation of the conus region overlying the pulmonary outflow tract[54]. This region was blocked by internal septae, thereby preventing the flow of blood to the lungs and resulting in a failure of pulmonary gas exchange and perinatal death. Heterozygous animals are viable and have grossly normal hearts, but ventricular epicardial conduction
Cx46 and Cx50 KO mice have cataracts
Both Cx46 KO[58]and Cx50 KO (T. W. White, D. A. Goodenough and D. P. Paul, unpublished) mice develop cataracts, but the timing, morphology and lens growth characteristics are not identical. Lens fibres are highly differentiated cells that lose their organelles and accumulate high concentrations of crystallins in order to maintain proper optical transparency and refractive index. Cx46 and Cx50 are expressed in the lens fibres and are responsible for joining the cells into a functional syncytium.
Concluding remarks
A consistent feature of the connexin KO and human disease phenotypes is the rather restricted nature of the defects observed, even though in some cases the connexins involved are expressed quite widely. Most cells express more than one connexin, and, to some extent, these connexins could have overlapping functions. Since the targeted connexin genes have a simple structure and thus are not alternatively spliced in different cell types, the observation that phenotypes resulting from connexin
Acknowledgements
We thank David L. Paul for long-standing collaborative efforts and Tom White and D. L. P. for comments on the manuscript. We also thank Guy A. Perkins and Gina E. Sosinsky for providing the image of the docking interactions of connexons. Supported by GM18974, EY02430 to D. A. G. and GM37751 to D. L. P.
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