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At least 19 recordsLinked to original sources

PubMed1995

The gap junction proteins beta 1-connexin (connexin-32) and beta 2-connexin (connexin-26) can form heteromeric hemichannels.

Two different types of gap junction proteins, beta 1- and beta 2-connexin, were expressed in insect cells, either singly or together, using infection with recombinant baculovirus. Membrane fractions enriched in gap junction proteins were isolated, and connexons (hemichannels) were solubilized with detergent. These solubilized connexons were then run out on a gel filtration column which was capable of partially separating the two homomeric connexons. It was found that connexons from cells co-infected with both types of baculovirus ran together on this column, whereas connexons from cells infected separately and mixed before solubilization did not, suggesting that in the co-infected cells the two types of connexin are assembled into heteromeric hemichannels.

Animals↗

PubMed2001

trans-dominant inhibition of connexin-43 by mutant connexin-26: implications for dominant connexin disorders affecting epidermal differentiation.

Dominant mutations of GJB2-encoding connexin-26 (Cx26) have pleiotropic effects, causing either hearing impairment (HI) alone or in association with palmoplantar keratoderma (PPK/HI). We examined a British family with the latter phenotype and identified a new dominant GJB2 mutation predicted to eliminate the amino acid residue E42 (DeltaE42) in Cx26. To dissect the pathomechanisms that result in diverse phenotypes of dominant GJB2 mutations, we studied the effect of three Cx26 mutants (DeltaE42, D66H and R75W) identified in individuals with PPK/HI, and another (W44C) present in individuals with non-syndromic HI on gap junctional intercellular communication. We expressed mutant Cx26 alone and together with the epidermal connexins Cx26, Cx37 and Cx43 in paired Xenopus oocytes, and measured the intercellular coupling by dual voltage clamping. Homotypic expression of each connexin as well as co-expression of wild-type (wt) Cx26/wtCx43 and wtCx26/wtCx37 yielded variable, yet robust, levels of channel activity. However, all four Cx26 mutants were functionally impaired and failed to induce intercellular coupling. When co-expressed with wtCx26, all four mutants suppressed the wtCx26 channel activity consistent with a dominant inhibitory effect. However, only those Cx26 mutants associated with a skin phenotype also significantly (P<0.05) inhibited intercellular conductance of co-expressed wtCx43, indicating a direct interaction of mutant Cx26 units with wtCx43. These results demonstrate, for the first time, a trans-dominant negative effect of Cx26 mutants in vitro. Furthermore, they support a novel concept suggesting that the principal mechanism for manifestation of dominant GJB2 mutations in the skin is their dominant interference with the function of wtCx43. This assumption is further corroborated by our finding that Cx26 and Cx43 focally colocalize at gap junctional plaques in affected skin tissue of two carriers of DeltaE42.

Adolescent↗

PubMed2000

Immunogold evidence that neuronal gap junctions in adult rat brain and spinal cord contain connexin-36 but not connexin-32 or connexin-43.

Physiological and ultrastructural evidence indicates that gap junctions link many classes of neurons in mammalian central nervous system (CNS), allowing direct electrical and metabolic communication. Among at least six gap junction-forming connexin proteins in adult rat brain, connexin- (Cx) 32, Cx36, and Cx43 have been reported to occur in neurons. However, no connexin has been documented at ultrastructurally defined neuronal gap junctions. To address this question directly, freeze-fracture replica immunogold labeling (FRIL) and immunofluorescence (IF) were used to visualize the subcellular and regional localization of Cx36 in rat brain and spinal cord. Three antibodies were generated against different sequences in Cx36. By Western blotting, these antibodies detected protein at 36 and 66 kDa, corresponding to Cx36 monomer and dimer forms, respectively. After double-labeling for Cx36 and Cx43 by FRIL, neuronal gap junctions in inferior olive, spinal cord, and retina were consistently immunogold-labeled for Cx36, but none were labeled for Cx43. Conversely, Cx43 but not Cx36 was detected in astrocyte and ependymocyte gap junctions. In >250 Cx32/Cx43 single- and double-labeled replicas from 10 CNS regions, no neuronal gap junctions were labeled for either Cx32 or Cx43. Instead, Cx32 and Cx43 were restricted to glial gap junctions. By IF, Cx36 labeling was widely distributed in neuropil, including along dendritic processes and within neuronal somata. On the basis of FRIL identification of Cx36 in neuronal gap junctions and IF imaging of Cx36 throughout rat brain and spinal cord, neuronal gap junctions containing Cx36 appear to occur in sufficient density to provide widespread electrical and metabolic coupling in adult CNS.

Animals↗

PubMed1996

Colocalization of connexin 43 and connexin 45 but absence of connexin 40 in granulosa cell gap junctions of rat ovary.

The expression and localization of gap junction family proteins (connexins) were examined in nonstimulated and gonadotrophin-stimulated ovarian follicles of immature rats. Immunoblot and RNA blot analysis showed the presence of connexin (Cx) 43, Cx40 and Cx45 in ovarian tissue. Of these connexin proteins, Cx43 and Cx45 were identified by immunofluorescent microscopy between granulosa cells in characteristic expression patterns related to follicular developmental stages, while Cx40 was not expressed in granulosa cells but was detected in blood vessels in ovarian stroma. In some plaques of gap junction between granulosa cells, Cx45 was found to be colocalized with Cx43. In immunofluorescent microscopy, the expression of Cx43 was increased with follicular growth, but decreased after induction of ovulation by injection of human chorionic gonadotrophin. In contrast, the Cx45 protein was constantly expressed through follicular development; however, after ovulation, no staining of Cx45 was detected in the corpus luteum. Dual expression and the functional role of Cx43 and Cx45 in cell-to-cell communication in ovarian granulosa cells at various developmental stages were discussed.

Animals↗

PubMed1994

Differential control of connexin-32 and connexin-43 expression in thyroid epithelial cells: evidence for a direct relationship between connexin-32 expression and histiotypic morphogenesis.

Thyroid epithelial cells cultured either as a monolayer or in the form of follicles, rapidly reconstitute functional gap junctions (Gj). We previously reported that the thyroid Gj gating is regulated by TSH. We have now performed molecular analyses of Gj proteins 1) to detect the connexin(s) (Cx) that is expressed in thyroid epithelial cells, 2) to determine whether the expression of Cx is hormonally regulated, and 3) to analyze the relationship between Cx expression and histiotypic morphogenesis, i.e. folliculogenesis. Studies were carried out on thyrocytes freshly isolated from the gland and on corresponding thyrocytes after 1-7 days in culture as monolayers or in the form of reconstituted follicles. The Cx gene transcription products were analyzed by Northern blot using specific complementary DNA probes for Cx26, Cx32, and Cx43. Cx proteins were identified and estimated by Western blot and indirect immunofluorescence using polyclonal antipeptide antibodies. Cx32 and Cx43 proteins and their corresponding messenger RNA (mRNA) were detected in thyrocytes freshly isolated from the gland. Thyrocytes contained a high amount of the 1.6-kilobase Cx32 mRNA and only traces of the 3-kilobase Cx43 transcript. No Cx26 transcripts could be detected. Thyrocytes cultured at a density of 0.2-0.5 x 10(6) cells/cm2 in the absence of TSH formed monolayers. Surprisingly, monolayer cells lost Cx32 protein within 24 h, and their Cx32 mRNA content decreased from high to barely detectable levels; Cx32 protein was no longer detected throughout the 1-week culture period. On the contrary, Cx43 mRNA and Cx43 protein rapidly increased in monolayer cells to reach very high levels within 2-4 days. Thyrocytes cultured at the same density, but in the presence of TSH also rapidly lost Cx32, but as soon as they reorganized into follicular structures, reexpressed Cx32 at a level (in terms of protein and mRNA) comparable to that found in cells freshly extracted from the gland. As observed for cell monolayers, reconstituted follicles overexpressed Cx43. The Cx43 protein and Cx43 mRNA contents of cultured thyrocytes were 20- to 50-fold higher than those found in isolated thyrocytes at the outset of culture. When thyrocytes were cultured with TSH, but at a low density (< 0.2 x 10(6) cells/cm2) to prevent follicle formation, a TSH-dependent increase in Cx43 was observed in monolayer cells. However, TSH did not cause any reexpression of Cx32.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2005

Connexin-47 and connexin-32 in gap junctions of oligodendrocyte somata, myelin sheaths, paranodal loops and Schmidt-Lanterman incisures: implications for ionic homeostasis and potassium siphoning.

The subcellular distributions and co-associations of the gap junction-forming proteins connexin 47 and connexin 32 were investigated in oligodendrocytes of adult mouse and rat CNS. By confocal immunofluorescence light microscopy, abundant connexin 47 was co-localized with astrocytic connexin 43 on oligodendrocyte somata, and along myelinated fibers, whereas connexin 32 without connexin 47 was co-localized with contactin-associated protein (caspr) in paranodes. By thin-section transmission electron microscopy, connexin 47 immunolabeling was on the oligodendrocyte side of gap junctions between oligodendrocyte somata and astrocytes. By freeze-fracture replica immunogold labeling, large gap junctions between oligodendrocyte somata and astrocyte processes contained much more connexin 47 than connexin 32. Along surfaces of internodal myelin, connexin 47 was several times as abundant as connexin 32, and in the smallest gap junctions, often occurred without connexin 32. In contrast, connexin 32 was localized without connexin 47 in newly-described autologous gap junctions in Schmidt-Lanterman incisures and between paranodal loops bordering nodes of Ranvier. Thus, connexin 47 in adult rodent CNS is the most abundant connexin in most heterologous oligodendrocyte-to-astrocyte gap junctions, whereas connexin 32 is the predominant if not sole connexin in autologous ("reflexive") oligodendrocyte gap junctions. These results clarify the locations and connexin compositions of heterologous and autologous oligodendrocyte gap junctions, identify autologous gap junctions at paranodes as potential sites for modulating paranodal electrical properties, and reveal connexin 47-containing and connexin 32-containing gap junctions as conduits for long-distance intracellular and intercellular movement of ions and associated osmotic water. The autologous gap junctions may regulate paranodal electrical properties during saltatory conduction. Acting in series and in parallel, autologous and heterologous oligodendrocyte gap junctions provide essential pathways for intra- and intercellular ionic homeostasis.

Animals↗

PubMed1997

Evidence for the co-localization of another connexin with connexin-43 at astrocytic gap junctions in rat brain.

Gap junctions between astrocytes as well as between astrocytes and oligodendrocytes in rat brain were immunohistochemically labelled with a monoclonal and an affinity-purified polyclonal antibody generated against connexin-26. By light microscopy, the immunolabelling patterns obtained were, with a few exceptions, remarkably similar to previously described distribution patterns of the gap junctional protein connexin-43, which is expressed by astrocytes and is localized at astrocytic gap junctions. By electron microscopy, immunoreactivity with these two anti-connexin-26 antibodies was restricted to astrocytes; inter-astrocytic gap junctional membranes were symmetrically labelled, heterologous oligo-astrocytic junctional membranes were asymmetrically labelled only on the astrocyte side and oligo-oligodendrocyte junctions were unlabelled. Two additional anti-connexin-26 antibodies that were found to produce punctate labelling in leptomeninges and liver failed to do so in brain parenchyma, consistent with reports indicating the absence of authentic connexin-26 in this tissue. Antibodies that labelled astrocytic gap junctions exhibited no cross-reaction with connexin-43 or connexin-32, as demonstrated by western blotting, but recognized liver connexin-26 as well as several brain proteins, including an approximately 32000 mol. wt protein that did not correspond to connexin-32 and a 26000 mol. wt protein that co-migrated with liver connexin-26. These results suggest that connexin-26, or more likely a protein having sequence homology with connexin-26, is targeted to astrocytic gap junctions and raise the possibility of the existence of connexins that may be co-expressed with connexin-43 in most, but perhaps not all, astrocytes.

Animals↗

PubMed1999

Loss of alpha 1 connexin does not alter the prenatal differentiation of pancreatic beta cells and leads to the identification of another islet cell connexin.

Connexin alpha 1, also referred to as Cx43, has thus far been the only gap junction protein identified between the hormone-producing cells of pancreatic islets. To investigate whether loss of this connexin affects the development of endocrine pancreas and the differentiation of insulin-producing beta cells, we have taken advantage of a transgenic line in which the gene coding for connexin alpha 1 had been functionally deleted by homologous recombination. Analysis of pancreas at embryonal day 19.5 (E 19.5) after immunostaining for the four main types of islet hormones, showed that islet cell development was similar in homozygous transgenic mice that completely lacked alpha 1 connexin, in mice that were heterozygous for the transgene, and in age-matched controls with a genetic background similar to that of the transgenic animals. In particular, the three animal groups featured beta cells that had a similar insulin content and ultrastructural organization, including the presence of typical gap junction plaques on the membrane. However, quantitative analysis of freeze-fractured membranes showed that these plaques were less frequent in the transgenic mice lacking alpha 1 connexin. This finding prompted us to revisit the connexin pattern of normal pancreatic beta cells. Using RT-PCR amplification and primers specific for nine of the mammalian connexins, we have found that normal rat and mouse pancreas contain six connexin transcripts, including one that codes for alpha 6 connexin, a protein also referred to as Cx45. This transcript was also identified in isolated pancreatic islets, in FACS-purified suspensions of primary beta cells and in the insulin-producing cells of an experimental tumor. Using antibodies, we found that connexin alpha 6 is expressed by the latter cells, as well as by pancreatic fibroblasts and epithelial duct cells. The data show that pancreatic islets have a normal prenatal development in mice that no longer express alpha 1 connexin. They further provide evidence that normal and tumoral insulin-producing cells natively coexpress connexins alpha 1 and alpha 6.

Animals↗

PubMed1996

Multiple connexin proteins in single intercellular channels: connexin compatibility and functional consequences.

In vertebrates, the protein subunits of intercellular channels found in gap junctions are encoded by a family of genes called connexins. These channels span two plasma membranes and result from the association of two half channels, or connexons, which are hexameric assemblies of connexins. Physiological analysis of channel formation and gating has revealed unique patterns of connexin-connexin interaction, and uncovered novel functional characteristics of channels containing more than one type of connexin protein. Structure-function studies have further demonstrated that unique domains within connexins participate in the regulation of different functional properties of intercellular channels. Thus, gap junctional channels can contain more than one connexin, and this structural heterogeneity has functional consequences in vitro. Moreover, emerging evidence for the existence of intercellular channels containing multiple connexins in native tissues suggests that the functional diversity generated by connexin-connexin interaction could contribute to complex communication patterns that have been observed in vivo.

Animals↗

PubMed2000

UltraRapid communication : coexpression of connexins 40 and 43 enhances the pH sensitivityof gap junctions: A model for synergistic interactions among connexins

Gap junctions are formed by oligomerization of a protein called connexin. Most cells express more than one connexin isotype. Atrial myocytes, for example, coexpress connexin (Cx) 40 and Cx43. The consequence of connexin coexpression on the regulation of gap junctions is not well understood. In the present study, we show that cells coexpressing Cx40 and Cx43 are more susceptible to acidification-induced uncoupling than those cells expressing only one connexin isotype. Xenopus oocytes were injected with mRNA for Cx40, Cx43, or a combination of both. Intracellular pH and junctional conductance were simultaneously measured while cells were progressively acidified by superfusion with a bicarbonate-buffered solution gassed with increasing concentrations of carbon dioxide. The data show that the pKa (ie, the pH at which junctional conductance decreased to 50% from maximum) shifted from approximately 6.7 when cells expressed only Cx40 or only Cx43 to approximately 7.0 when one of the oocytes was coexpressing both connexins. Truncation of the carboxyl terminal domains of the connexins caused the loss of pH sensitivity even after coexpression. The data are interpreted on the basis of previous studies from our laboratory that demonstrated heterodomain interactions in the regulation of Cx40 and Cx43 gap junctions. The possible implications of these findings on the regulation of native gap junctions that express both connexins remain to be determined. The full text of this article is available at http://www.circresaha.org. Web Site Feature The full-length article can be found on the World Wide Web at http://www.circresaha.org Key Words: connexin gap junctions pH(i)

Journal Article↗

PubMed2003

Targeted epidermal expression of mutant Connexin 26(D66H) mimics true Vohwinkel syndrome and provides a model for the pathogenesis of dominant connexin disorders.

To investigate the role of connexins in dominantly inherited skin disease, transgenic mice were produced which expressed mutant connexin 26 [gjb2/connexin 26(D66H)], from a keratin 10 promoter, exclusively in the suprabasal epidermis (the cells in which Connexin 26 is up-regulated in epidermal hyperproliferative states). From soon after birth, the mice exhibited a keratoderma similar to that in humans carrying the Connexin 26(D66H) mutation (true Vohwinkel syndrome). Transgene expression was associated with loss of Connexin 26 and Connexin 30 from epidermal keratinocyte intercellular junctions and accumulation in cytoplasm. Light and electron microscopy showed marked thickening of the epidermal cornified layers and increased epidermal TUNEL staining, indicative of premature keratinocyte programmed cell death. The K10Connexin 26(D66H) mouse may provide a valuable model to study the role of gap-junctional intercellular communication in epidermal differentiation. Similarities in phenotype between individuals (man and mouse) carrying Connexin 26(D66H) and those carrying insertional mutants of Loricrin, a major cornified envelope protein of the epidermis, suggest a possible link between connexin function and cornified envelope formation.

Animals↗

PubMed2000

Coexpression of connexins 40 and 43 enhances the pH sensitivity of gap junctions: a model for synergistic interactions among connexins.

Animals↗

PubMedDate not supplied

Connexin channels, connexin mimetic peptides and ATP release.

Connexin hemichannels, that is, half gap junction channels (not connecting cells), have been implicated in the release of various messengers such as ATP and glutamate. We used connexin mimetic peptides, which are, small peptides mimicking a sequence on the connexin subunit, to investigate hemichannel functioning in endothelial cell lines. Short exposure (30 min) to synthetic peptides mimicking a sequence on the first or second extracellular loop of the connexin subunit strongly supressed ATP release and dye uptake triggered by either intracellular InsP(3) elevation or exposure to zero extracellular calcium, while gap junctional coupling was not affected under these conditions. The effect was dependent on the expression of connexin-43 in the cells. Connexin mimetic peptides thus appear to be interesting tools to distinguish connexin hemichannel from gap junction channel functioning. In addition, they are well suited to further explore the role of connexins in cellular release or uptake processes, to investigate hemichannel gating and to reveal new unknown functions of the large conductance hemichannel pathway between the cell and its environment. Work performed up to now with these peptides should be re-interpreted in terms of these new findings.

Adenosine Triphosphate↗

PubMed1994

Selective interactions among the multiple connexin proteins expressed in the vertebrate lens: the second extracellular domain is a determinant of compatibility between connexins.

Gap junctions are collections of intercellular channels composed of structural proteins called connexins (Cx). We have examined the functional interactions of the three rodent connexins present in the lens, Cx43, Cx46, and Cx50, by expressing them in paired Xenopus oocytes. Homotypic channels containing Cx43, Cx46, or Cx50 all developed high conductance. heterotypic channels composed of Cx46 paired with either Cx43 or Cx50 were also well coupled, whereas Cx50 did not form functional channels with Cx43. We also examined the functional response of homotypic and heterotypic channels to transjunctional voltage and cytoplasmic acidification. We show that all lens connexins exhibited sensitivity to cytoplasmic acidification as well as to voltage, and that voltage-dependent closure of heterotypic channels for a given connexin was dramatically influenced by its partner connexins in the adjacent cell. Based on the observation that Cx43 can discriminate between Cx46 and Cx50, we investigated the molecular determinants that specify compatibility by constructing chimeric connexins from portions of Cx46 and Cx50 and testing them for their ability to form channels with Cx43. When the second extracellular (E2) domain in Cx46 was replaced with the E2 of Cx50, the resulting chimera could no longer form heterotypic channels with Cx43. A reciprocal chimera, where the E2 of Cx46 was inserted into Cx50, acquired the ability to functionally interact with Cx43. Together, these results demonstrate that formation of intercellular channels is a selective process dependent on the identity of the connexins expressed in adjacent cells, and that the second extracellular domain is a determinant of heterotypic compatibility between connexins.

Amino Acid Sequence↗

PubMed1995

Negative growth control of HeLa cells by connexin genes: connexin species specificity.

In order to examine whether different connexin gene species exert different degrees of tumor-suppressing activity, we characterized growth characteristics of a gap junction-deficient human cancer cell line, HeLa cells, before and after transfection with cDNA for three different connexins, connexin (cx) 26, cx 40, and cx 43. All transfected cell lines (3 clones transfected with the cx 26 gene, 2 clones with cx 40, and 1 with cx 43) showed establishment of gap junctional intercellular communication (GJIC). Two of the cx 26-transfected clones showed significantly slower growth compared with the parental HeLa cells. When transfectants were grown in soft agar, the three cx 26-transfected clones grew much less than the other transfectants and parent HeLa cells. When injected into nude mice, the two cx 26 clones which exhibited the highest amount of cx 26 transcript induced almost no tumors, whereas other transfectants, including the cx 26 clone which exhibited the lowest amount of cx 26 transcript, were tumorigenic. Among transfectants of various connexin genes, there was no good inverse correlation between their GJIC and tumorigenicity. GJIC levels were significantly higher in tumors induced in nude mice by clone cx 26 A and E transfectants. These results suggest that all of the connexin genes examined could induce recovery of GJIC of HeLa cells, but only the cx 26 gene exerts strong negative growth control on HeLa cells; thus, this connexin gene may have different functions from other connexin genes.

Animals↗

PubMed2000

Connexins, hearing and deafness: clinical aspects of mutations in the connexin 26 gene.

Congenital deafness is a very frequent disorder occurring in approximately I in 1000 live births. Mutations in GJB2 encoding for gap junction protein connexin-26 (Cx26) have been established as the basis of autosomal recessive non-syndromic hearing loss and proposed in some rare cases of autosomal dominant form of deafness. Connexin are gap-junction proteins which constitute a major system of intercellular communication important in the exchange of electrolytes, second messengers and metabolites. In the inner ear, connexin 26 expression was demonstrated in the stria vascularis, basement membrane, limbus and the spiral prominence of the human cochlea. The loss of connexin 26 in the gap junction complex would expect to disrupt the recycling of potassium from the synapses at the base of hair cells through the supporting cells and fibroblasts of potassium ions back to the high potassium containing endolymph of the cochlear duct and therefore would result in a local intoxication of the Corti s organ by potassium, leading to the hearing loss. The discovery of the genes responsible of hearing loss in particular the identification of mutations in the gene coding for connexin 26 allows to hope some tremendous help in genetic counseling. The possible implication of the mutation of the connexin gene in the pathophysiology of some progressive adult deafness opens new prospects in the fine diagnostic of the ear diseases and eventually may lead to new therapeutic strategies applied to the cochlea.

Adult↗

PubMed1998

Expression of gap junction proteins connexin 26 and connexin 43 in normal human breast and in breast tumours.

Gap junctional intercellular communication (GJIC) has been proposed as a cellular mechanism for tumour suppression and there is experimental evidence in support of this. If aberrant GJIC contributes to the formation of human breast tumours, one might expect that the connexins (gap junction proteins) expressed by epithelial cells in normal human breast would be down-regulated in tumour epithelial cells, or that tumour cells might show aberrant expression of other connexin family members. This study examines the immunocytochemical expression of connexins 26 (Cx26) and 43 (Cx43) in normal human breast, 11 benign breast lesions, two special-type carcinomas, and 27 invasive carcinomas of no special histological type (NST). Cx26 generally was not expressed at detectable level in normal human breast, but punctate Cx43 immunostaining of the myoepithelial cells was found. Cx43 staining of the myoepithelium was also a feature of the benign lesions and ductal carcinoma in situ (DCIS). In general, the epithelial cells of benign lesions failed to stain for either connexin. Similarly, a lobular carcinoma did not express Cx26 or Cx43, but there was punctate Cx43 in the epithelial cells of a mucoid carcinoma. Cx26 was up-regulated in the carcinoma cells of 15 of the 27 invasive NST carcinomas, although the staining was usually cytoplasmic and heterogeneous. Cx43 was expressed by stromal cells, possibly myofibroblasts, in all NST carcinomas. Furthermore, there was heterogeneous Cx43 expression in the carcinoma cells of 14 of the 27 NST carcinomas and the staining was often intercellular and punctate, characteristic of functional connexins. Up-regulated of Cx26 and/or Cx43 in the carcinoma cells of over two-thirds of invasive lesions of NST is not necessarily inconsistent with a tumour suppressor role for GJIC. However, the role of gap junctions in the formation and progression of solid human tumours is likely to be more complex than indicated from experimental systems.

Breast↗

PubMed2002

Heterogeneous expression of connexins in rabbit sinoatrial node cells: correlation between connexin isotype and cell size.

OBJECTIVE: Intercellular coupling through gap junctions allows the morphologically and functionally heterogeneous sinoatrial node to synchronize and drive the atrial muscle. The purpose of this study was to identify the connexin isotypes expressed by sinoatrial node cells and to analyse the density of connexins in relation to cell size. METHODS: Labeling for the different connexins using isotype-specific antibodies was assessed in cells isolated from the rabbit sinoatrial node by immunoconfocal microscopy. RESULTS: Sinoatrial node cells with a cell projection area smaller than 800 microm(2) were devoid of immunolabeling for connexin43. Such small cells showed high levels of connexin45 labeling (compared to that in large cells) and low levels of connexin40 labeling. Sinoatrial node cells with a projection area between 800 and 1200 microm(2) had a lower amount of connexin45 label and again a small amount of connexin40 but an increased amount of connexin43 label. In the larger sinoatrial node cells, some colocalization of connexin45 and connexin43 immunolabeled spots was observed. CONCLUSIONS: Rabbit sinoatrial node cells are heterogeneous in terms of connexin expression, and there is a clear cell size-dependence in pattern of connexin expression. Small (putative central) cells express connexin45 but not connexin43, whereas larger (putative peripheral) cells express both connexin45 and connexin43. The co-localization of connexin43 and connexin45 in larger cells raises the possibility that heterotypic or heteromeric connexin43/connexin45 channels could be present in gap junctions at the periphery of the sinoatrial node.

Animals↗