scholarly journals Upregulated Connexin 43 Induced by Loss-of-Functional S284L-Mutant α4 Subunit of Nicotinic ACh Receptor Contributes to Pathomechanisms of Autosomal Dominant Sleep-Related Hypermotor Epilepsy

2020 ◽  
Vol 13 (4) ◽  
pp. 58 ◽  
Author(s):  
Kouji Fukuyama ◽  
Masashi Fukuzawa ◽  
Ruri Okubo ◽  
Motohiro Okada
Keyword(s):  
Connexin 43 ◽  
Autosomal Dominant ◽  
Glutamatergic Transmission ◽  
Wild Type ◽  
Thalamic Nuclei ◽  
Cx43 Expression ◽  
Motor Pathway ◽  
Nicotine Administration ◽  
Cultured Astrocytes ◽  
Primary Cultured Astrocytes

To study the pathomechanism and pathophysiology of autosomal dominant sleep-related hypermotor epilepsy (ADSHE), this study determined functional abnormalities of glutamatergic transmission in the thalamocortical motor pathway, from the reticular thalamic nucleus (RTN), motor thalamic nuclei (MoTN) tosecondary motor cortex (M2C) associated with the S286L-mutant α4β2-nicotinic acetylcholine receptor (nAChR) and the connexin43 (Cx43) hemichannel of transgenic rats bearing the rat S286L-mutant Chrna4 gene (S286L-TG), which corresponds to the human S284L-mutant CHRNA4 gene using multiprobe microdialysis, primary cultured astrocytes and a Simple Western system. Expression of Cx43 in the M2C plasma membrane fraction of S286L-TG was upregulated compared with wild-type rats. Subchronic nicotine administration decreased Cx43 expression of wild-type, but did not affect that of S286L-TG; however, zonisamide (ZNS) decreased Cx43 in both wild-type and S286L-TG. Primary cultured astrocytes of wild-type were not affected by subchronic administration of nicotine but was decreased by ZNS. Upregulated Cx43 enhanced glutamatergic transmission during both resting and hyperexcitable stages in S286L-TG. Furthermore, activation of glutamatergic transmission associated with upregulated Cx43 reinforced the prolonged Cx43 hemichannel activation. Subchronic administration of therapeutic-relevant doses of ZNS compensated the upregulation of Cx43 and prolonged reinforced activation of Cx43 hemichannel induced by physiological hyperexcitability during the non-rapid eye movement phase of sleep. The present results support the primary pathomechanisms and secondary pathophysiology of ADSHE seizures of patients with S284L-mutation.

scholarly journals Age-Dependent and Sleep/Seizure-Induced Pathomechanisms of Autosomal Dominant Sleep-Related Hypermotor Epilepsy

2020 ◽  
Vol 21 (21) ◽  
pp. 8142 ◽  
Author(s):  
Kouji Fukuyama ◽  
Motohiro Okada
Keyword(s):  
Plasma Membrane ◽  
Autosomal Dominant ◽  
Loss Of Function ◽  
Glutamatergic Transmission ◽  
Wild Type ◽  
Cx43 Expression ◽  
Nicotine Administration ◽  
Extracellular Signal ◽  
Age Dependent ◽  
Before And After

The loss-of-function S284L-mutant α4 subunit of the nicotinic acetylcholine receptor (nAChR) is considered to contribute to the pathomechanism of autosomal dominant sleep-related hypermotor epilepsy (ADSHE); however, the age-dependent and sleep-related pathomechanisms of ADSHE remain to be clarified. To explore the age-dependent and sleep-induced pathomechanism of ADSHE, the present study determined the glutamatergic transmission abnormalities associated with α4β2-nAChR and the astroglial hemichannel in the hyperdirect and corticostriatal pathways of ADSHE model transgenic rats (S286L-TG) bearing the rat S286L-mutant Chrna4 gene corresponding to the human S284L-mutant CHRNA4 gene of ADSHE, using multiprobe microdialysis and capillary immunoblotting analyses. This study could not detect glutamatergic transmission in the corticostriatal pathway from the orbitofrontal cortex (OFC) to the striatum. Before ADSHE onset (four weeks of age), functional abnormalities of glutamatergic transmission compared to the wild-type in the cortical hyperdirect pathway, from OFC to the subthalamic nucleus (STN) in S286L-TG, could not be detected. Conversely, after ADSHE onset (eight weeks of age), glutamatergic transmission in the hyperdirect pathway of S286L-TG was enhanced compared to the wild-type. Notably, enhanced glutamatergic transmission of S286L-TG was revealed by hemichannel activation in the OFC. Expression of connexin43 (Cx43) in the OFC of S286L-TG was upregulated after ADSHE onset but was almost equal to the wild-type prior to ADSHE onset. Differences in the expression of phosphorylated protein kinase B (pAkt) before ADSHE onset between the wild-type and S286L-TG were not observed; however, after ADSHE onset, pAkt was upregulated in S286L-TG. Conversely, the expression of phosphorylated extracellular signal-regulated kinase (pErk) was already upregulated before ADSHE onset compared to the wild-type. Both before and after ADSHE onset, subchronic nicotine administration decreased and did not affect the both expression of Cx43 and pErk of respective wild-type and S286L-TG, whereas the pAkt expression of both the wild-type and S286L-TG was increased by nicotine. Cx43 expression in the plasma membrane of the primary cultured astrocytes of the wild-type was increased by elevation of the extracellular K+ level (higher than 10 mM), and the increase in Cx43 expression in the plasma membrane required pErk functions. These observations indicate that a combination of functional abnormalities, GABAergic disinhibition, and upregulated pErk induced by the loss-of-function S286L-mutant α4β2-nAChR contribute to the age-dependent and sleep-induced pathomechanism of ADSHE via the upregulation/hyperactivation of the Cx43 hemichannels.

scholarly journals Upregulated and Hyperactivated Thalamic Connexin 43 Plays Important Roles in Pathomechanisms of Cognitive Impairment and Seizure of Autosomal Dominant Sleep-Related Hypermotor Epilepsy with S284L-Mutant α4 Subunit of Nicotinic ACh Receptor

2020 ◽  
Vol 13 (5) ◽  
pp. 99 ◽  
Author(s):  
Kouji Fukuyama ◽  
Masashi Fukuzawa ◽  
Motohiro Okada
Keyword(s):  
Connexin 43 ◽  
Cognitive Deficit ◽  
Autosomal Dominant ◽  
Thalamic Nucleus ◽  
Glutamate Release ◽  
Glutamatergic Transmission ◽  
Transgenic Rats ◽  
Cx43 Expression ◽  
Mediodorsal Thalamic Nucleus ◽  
Thalamocortical Pathway

To understand the pathomechanism and pathophysiology of autosomal dominant sleep-related hypermotor epilepsy (ADSHE), we studied functional abnormalities of glutamatergic transmission in thalamocortical pathway from reticular thalamic nucleus (RTN), mediodorsal thalamic nucleus (MDTN) to orbitofrontal cortex (OFC) associated with S286L-mutant α4β2-nicotinic acetylcholine receptor (nAChR), and connexin43 (Cx43) hemichannel of transgenic rats bearing rat S286L-mutant Chrna4 gene (S286L-TG), corresponding to the human S284L-mutant CHRNA4 gene using simple Western analysis and multiprobe microdialysis. Cx43 expression in the thalamic plasma membrane fraction of S286L-TG was upregulated compared with that of wild-type. Subchronic administrations of therapeutic-relevant doses of zonisamide (ZNS) and carbamazepine (CBZ) decreased and did not affect Cx43 expression of S286L-TG, respectively. Upregulated Cx43 enhanced glutamatergic transmission during both resting and hyperexcitable stages in S286L-TG. Furthermore, activation of GABAergic transmission RTN–MDTN pathway conversely enhanced, but not inhibited, l-glutamate release in the MDTN via upregulated/activated Cx43. Local administration of therapeutic-relevant concentration of ZNS and CBZ acutely supressed and did not affect glutamatergic transmission in the thalamocortical pathway, respectively. These results suggest that pathomechanisms of ADSHE seizure and its cognitive deficit comorbidity, as well as pathophysiology of CBZ-resistant/ZNS-sensitive ADSHE seizures of patients with S284L-mutation.

scholarly journals Effects of Carbamazepine, Lacosamide and Zonisamide on Gliotransmitter Release Associated with Activated Astroglial Hemichannels

2020 ◽  
Vol 13 (6) ◽  
pp. 117 ◽  
Author(s):  
Kouji Fukuyama ◽  
Yuto Ueda ◽  
Motohiro Okada
Keyword(s):  
Orbitofrontal Cortex ◽  
Partial Epilepsy ◽  
Na Channel ◽  
The Novel ◽  
Cx43 Expression ◽  
Cultured Astrocytes ◽  
Voltage Dependent ◽  
Relevant Dose ◽  
Cognitive Disturbance ◽  
Primary Cultured Astrocytes

Recent studies using the genetic partial epilepsy model have demonstrated that hyperfunction of astroglial hemichannels contributes to pathomechanism of epileptic seizure. Therefore, to explore the novel anticonvulsive mechanisms, the present study determined the effects of voltage-dependent Na+ channel (VDSC)-inhibiting anticonvulsants, carbamazepine (CBZ), lacosamide (LCM), and zonisamide (ZNS) on the astroglial release of l-glutamate and adenosine triphosphate (ATP). The effects of subchronic administration of therapeutic-relevant dose of three anticonvulsants on the release of l-glutamate and ATP in the orbitofrontal cortex (OFC) were determined using microdialysis. The concentration-dependent effects of acute and subchronic administrations of anticonvulsants on astroglial gliotransmitter release were determined using primary cultured astrocytes. The concentration-dependent effects of subchronic administrations of anticonvulsants on connexin43 (Cx43) expression in the plasma membrane of primary cultured astrocytes were determined using the Simple Western system. An increase in the levels of extracellular K+ resulted in a concentration-dependent increase in the astroglial release of l-glutamate and ATP. The depleted levels of extracellular Ca2+ alone did not affect astroglial gliotransmitter release but did accelerate K+-evoked gliotransmitter release via activation of astroglial hemichannels. Both non-selective hemichannel inhibitor carbenoxolone (CBX) and selective Cx43 inhibitor GAP19 prevented both gliotransmitter release through activated astroglial hemichannels and the hemichannel-activating process induced by elevation of the levels of extracellular K+ with depletion of the levels of extracellular Ca2+. ZNS subchronically decreased Cx43 expression and acutely/subchronically inhibited Cx43 hemichannel activity. LCM acutely inhibited hemichannel activity but did not subchronically affect Cx43 expression. Therapeutic-relevant concentration of CBZ did not affect hemichannel activity or Cx43 expression, but supratherapeutic concentration of CBZ decreased Cx43 expression and hemichannel activity. Therefore, the present study demonstrated the distinct effects of CBZ, LCM, and ZNS on gliotransmitter release via modulation of astroglial hemichannel function. The different features of the effects of three VDSC-inhibiting anticonvulsants on astroglial transmission associated with hemichannels, at least partially, possibly contributing to the formation of the properties of these three anticonvulsants, including the antiepileptic spectrum and adverse effects regarding mood and cognitive disturbance.

Dissection of the Role of Connexin-43 in Hematopoietic Progenitors and Stromal Cells Unveils Distinct Hematopoietic Intrinsic and Extrinsic Regulatory Functions.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 607-607
Author(s):  
Lina Li ◽  
Bhuvana Murali ◽  
Dealma N. Worsham ◽  
Susan K. Dunn ◽  
Jose A. Cancelas
Keyword(s):  
Bone Marrow ◽  
Stromal Cells ◽  
Connexin 43 ◽  
Chimeric Mice ◽  
Wild Type ◽  
Hematopoietic Progenitors ◽  
Hematopoietic Progenitor ◽  
Cx43 Expression

Abstract Bone marrow (BM) stromal cells seem to be crucial in the establishment of the hematopoietic niches in bone marrow. BM stromal cells can communicate through gap junctions, which consist of narrow channels between contacting cells and are composed by connexins. Connexin 43 (Cx43) is expressed by BM stromal cells and upon adhesion to stroma, by hematopoietic stem cells and progenitors (HSC/P). Cx43 has been shown to be essential in controlling osteoblast and fibroblast function. We have previously reported that Cx43 is critical for the interaction between stroma and HSC/P in CAFC assays (Cancelas J.A. et al., Blood 2000) and in adult hematopoiesis after 5-fluorouracil (5-FU) administration in Mx1-Cre-Tg;Cx43KO mice (Presley C, et al., Cell Comm. Adh., 2005). We have also previously shown that after 5-FU administration, Cx43 is predominantly expressed in the endosteum and the deficiency of Cx43 in stroma of Collagen I (ColI)-Cre;Cx43KO and chimeric mice impairs their hematopoiesis by impairing the homing of wild-type (WT) hematopoietic progenitors and after 5-FU administration, the hematopoietic progenitor cycling inducing a ∼30% expansion of the long-term stem cell compartment in BM (Li L et al., ASH 2006). Interestingly, stromal Cx43-deficient mice contain around twice as many CFU-F as wild-type (WT) mice. Now, we have further investigated the role of stromal Cx43 expression in the regulation of hematopoietic progenitor adhesion to stroma, trans-stromal migration and mobilization. Cx43-deficient stromal cells display complete absence of intercellular communication as assayed by calcein dye transfer which can be reverted by retroviral transduction of Cx43. Trans-stromal migration of hematopoietic progenitors through Cx43-deficient irradiated stroma is impaired (7.8% vs 13.8% in WT stroma, p=0.015) but primary adhesion to Cx43-deficient irradiated stroma and in vivo mobilization response to G-CSF in ColI-Cre;Cx43KO mice were similar to WT controls, suggesting that stromal Cx43 plays a role in the regulation of the post-adhesion migration of HSC/P. On the other hand, Cx43-deficient HSC/P from Vav1-Cre;Cx43KO primary and chimeric mice show severe impairment of blood cell formation during the recovery phase after 5-FU administration (day +14) compared to wild-type controls (ANC: 0.23±0.12 vs 1.40±1.25 x 109 neutrophils/L; Platelet count: 135±91 vs 572±205 x 109 platelets/L; p < 0.05). Cx43 deficiency in hematopoietic progenitors did not significantly impair their homing ability in wild-type mice. Taken together, these studies indicate that Cx43 expression plays distinct roles in the regulation of hematopoietic intrinsic and extrinsic mechanisms. While Cx43 expression in stroma seems to be crucial in the regulation of the stromal progenitor and HSC pool content as well as HSC/P trans-stromal migration and homing, deficiency of Cx43 in either hematopoietic cells or stromal cells independently induce a significant impairment in the post-chemotherapy blood formation in vivo, suggesting that, under stress, hematopoietic regeneration depends on complete Cx43 channels communicating HSC/P and stromal cells.

Phosphorylation of connexin 43 induced by traumatic brain injury promotes exosome release

2018 ◽  
Vol 119 (1) ◽  
pp. 305-311 ◽  
Author(s):  
Wei Chen ◽  
Yijun Guo ◽  
Wenjin Yang ◽  
Lei Chen ◽  
Dabin Ren ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Gap Junction ◽  
Connexin 43 ◽  
Hippocampal Slices ◽  
Long Term Potentiation ◽  
Cx43 Expression ◽  
Term Potentiation ◽  
Junction Protein

Traumatic brain injury (TBI) caused by the external force leads to the neuronal dysfunction and even death. TBI has been reported to significantly increase the phosphorylation of glial gap junction protein connexin 43 (Cx43), which in turn propagates damages into surrounding brain tissues. However, the neuroprotective and anti-apoptosis effects of glia-derived exosomes have also been implicated in recent studies. Therefore, we detected whether TBI-induced phosphorylation of Cx43 would promote exosome release in rat brain. To generate TBI model, adult male Sprague-Dawley rats were subjected to lateral fluid percussion injury. Phosphorylated Cx43 protein levels and exosome activities were quantified using Western blot analysis following TBI. Long-term potentiation (LTP) was also tested in rat hippocampal slices. TBI significantly increased the phosphorylated Cx43 and exosome markers expression in rat ipsilateral hippocampus, but not cortex. Blocking the activity of Cx43 or ERK, but not JNK, significantly suppressed TBI-induced exosome release in hippocampus. Furthermore, TBI significantly inhibited the induction of LTP in hippocampal slices, which could be partially but significantly restored by pretreatment with exosomes. The results imply that TBI-activated Cx43 could mediate a nociceptive effect by propagating the brain damages, as well as a neuroprotective effect by promoting exosome release. NEW & NOTEWORTHY We have demonstrated in rat traumatic brain injury (TBI) models that both phosphorylated connexin 43 (p-Cx43) expression and exosome release were elevated in the hippocampus following TBI. The promoted exosome release depends on the phosphorylation of Cx43 and requires ERK signaling activation. Exosome treatment could partially restore the attenuated long-term potentiation. Our results provide new insight for future therapeutic direction on the functional recovery of TBI by promoting p-Cx43-dependent exosome release but limiting the gap junction-mediated bystander effect.

scholarly journals Decreased connexin43 expression in the mouse heart potentiates pacing-induced remodeling of repolarizing currents

2008 ◽  
Vol 295 (5) ◽  
pp. H1905-H1916 ◽  
Author(s):  
Andrianos Kontogeorgis ◽  
Xiaodong Li ◽  
Eunice Y. Kang ◽  
Jonathan E. Feig ◽  
Marc Ponzio ◽  
...  
Keyword(s):  
Gap Junction ◽  
Ventricular Myocytes ◽  
Critical Role ◽  
Mouse Heart ◽  
Wild Type ◽  
Short Term ◽  
Wild Type Littermate ◽  
Cx43 Expression ◽  
Significant Prolongation ◽  
Electrophysiological Effects

Gap junction redistribution and reduced expression, a phenomenon termed gap junction remodeling (GJR), is often seen in diseased hearts and may predispose toward arrhythmias. We have recently shown that short-term pacing in the mouse is associated with changes in connexin43 (Cx43) expression and localization but not with increased inducibility into sustained arrhythmias. We hypothesized that short-term pacing, if imposed on murine hearts with decreased Cx43 abundance, could serve as a model for evaluating the electrophysiological effects of GJR. We paced wild-type (normal Cx43 abundance) and heterozygous Cx43 knockout (Cx43+/−; 66% mean reduction in Cx43) mice for 6 h at 10–15% above their average sinus rate. We investigated the electrophysiological effects of pacing on the whole animal using programmed electrical stimulation and in isolated ventricular myocytes with patch-clamp studies. Cx43+/− myocytes had significantly shorter action potential durations (APD) and increased steady-state ( Iss) and inward rectifier ( IK1) potassium currents compared with those of wild-type littermate cells. In Cx43+/− hearts, pacing resulted in a significant prolongation of ventricular effective refractory period and APD and significant diminution of Iss compared with unpaced Cx43+/− hearts. However, these changes were not seen in paced wild-type mice. These data suggest that Cx43 abundance plays a critical role in regulating currents involved in myocardial repolarization and their response to pacing. Our study may aid in understanding how dyssynchronous activation of diseased, Cx43-deficient myocardial tissue can lead to electrophysiological changes, which may contribute to the worsened prognosis often associated with pacing in the failing heart.

Abstract 336: A 14-3-3 Mode-1 Binding Motif Promotes Gap Junction Internalization During Acute Cardiac Ischemia

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
James W Smyth ◽  
Jose M Sanchez ◽  
Samy Lamouille ◽  
Ting-Ting Hong ◽  
Jacob M Vogan ◽  
...  
Keyword(s):  
Gap Junction ◽  
Protein Trafficking ◽  
Connexin 43 ◽  
Electrical Coupling ◽  
Acute Ischemia ◽  
Binding Motif ◽  
Wild Type ◽  
Gap Junction Coupling ◽  
Junction Coupling ◽  
Cell Cell

During each heartbeat, robust cell-cell electrical coupling via connexin 43 (Cx43) gap junctions allows billions of individual cardiomyocytes to contract in synchrony. Cx43 turns over rapidly, and altered Cx43 trafficking during disease contributes to the arrhythmias of sudden cardiac death. The overall phosphorylation status of the Cx43 protein is known to regulate gap junction coupling, but the role of many residue specific phosphorylation events remains unknown. One such residue, Ser373, forms a mode-1 14-3-3 binding motif upon phosphorylation. Given that 14-3-3 proteins are known to regulate protein trafficking, we hypothesized a role for Cx43 Ser373 phosphorylation in regulation of Cx43 gap junction coupling. Using Langendorff-perfused mouse hearts we find robust phosphorylation of Cx43 at Ser373 and Ser368 after 30 min of no-flow ischemia. In human cell lines, a S373A mutation ablated Cx43/14-3-3 complexing and 35 S pulse-chase revealed Cx43 S373A also experiences a longer half-life than wild-type Cx43. Previous reports have implicated phosphorylation of Cx43 Ser368 in PKC mediated Cx43 internalization. We find that upon activation of PKC, the Cx43 S373A mutant undergoes lower and more transient levels of phosphorylation at Ser368 than wild-type Cx43. Consistent with these data, siRNA-mediated ablation of 14-3-3 expression results in enlargement of gap junction plaque formation at cell-cell borders. In conclusion, we propose that phosphorylation of Cx43 Ser373 results in 14-3-3 binding which promotes and maintains phosphorylation of Cx43 Ser368 and the subsequent internalization of gap junction channels. These results identify for the first time a specific role for 14-3-3 proteins in regulation of Cx43 internalization during acute ischemia and contribute to the development of therapies aimed at preserving or enhancing gap junction coupling in the heart.

Effects of ferulic acid on oxidative stress, heat shock protein 70, connexin 43, and monoamines in the hippocampus of pentylenetetrazole-kindled rats

2017 ◽  
Vol 95 (6) ◽  
pp. 732-742 ◽  
Author(s):  
Abdelaziz M. Hussein ◽  
Khaled M. Abbas ◽  
Osama A. Abulseoud ◽  
El-Hussainy M.A. El-Hussainy
Keyword(s):  
Oxidative Stress ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Ferulic Acid ◽  
Group Treatment ◽  
Heat Shock Protein 70 ◽  
Connexin 43 ◽  
Hsp70 Expression ◽  
Neuroprotective Effects ◽  
Cx43 Expression

The present study investigated the effects of ferulic acid (FA) on pentylenetetrazole (PTZ)-induced seizures, oxidative stress markers (malondialdehyde (MDA), catalase, and reduced glutathione (GSH)), connexin (Cx) 43, heat shock protein 70 (Hsp 70), and monoamines (serotonin (5-HT) and norepinephrine (NE)) levels in a rat model of PTZ-induced kindling. Sixty Sprague Dawley rats were divided into 5 equal groups: (a) normal group; (b) FA group: normal rats received FA at a dose of 40 mg/kg daily; (c) PTZ group: normal rats received PTZ at a dose of 50 mg/kg i.p. on alternate days for 15 days; (d) FA-before group: treatment was the same as for the PTZ group, except rats received FA; and (e) FA-after group: rats received FA from sixth dose of PTZ. PTZ caused a significant increase in MDA, Cx43, and Hsp70 along with a significant decrease in GSH, 5-HT, and NE levels and CAT activity in the hippocampus (p < 0.05). Pre- and post-treatment with FA caused significant improvement in behavioral parameters, MDA, CAT, GSH, 5-HT, NE, Cx43 expression, and Hsp70 expression in the hippocampal region (p < 0.05). We conclude that FA has neuroprotective effects in PTZ-induced epilepsy, which might be due to attenuation of oxidative stress and Cx43 expression and upregulation of neuroprotective Hsp70 and neurotransmitters (5-HT and NE).

scholarly journals Transforming growth factor-β1 up-regulates connexin43 expression in osteocytes via canonical Smad-dependent signaling pathway

2018 ◽  
Vol 38 (6) ◽  
Author(s):  
Wenjing Liu ◽  
Yujia Cui ◽  
Jianxun Sun ◽  
Linyi Cai ◽  
Jing Xie ◽  
...  
Keyword(s):  
Growth Factor ◽  
Connexin 43 ◽  
Transforming Growth Factor ◽  
Bone Cells ◽  
Underlying Mechanism ◽  
Transforming Growth Factor Β1 ◽  
Type I ◽  
Gap Junctional Intercellular Communication ◽  
Cx43 Expression ◽  
Tgf Β1

Connexin 43 (Cx43)-mediated gap junctional intercellular communication (GJIC) has been shown to be important in regulating multiple functions of bone cells. Transforming growth factor-β1 (TGF-β1) exhibited controversial effects on the expression of Cx43 in different cell types. To date, the effect of TGF-β1 on the Cx43 expression of osteocytes is still unknown. In the present study, we detected the expression of TGF-β1 in osteocytes and bone tissue, and then used recombinant mouse TGF-β1 to elucidate its effect on gap junctions (GJs) of osteocytes. Our data indicated that TGF-β1 up-regulated both mRNA and protein expression of Cx43 in osteocytes. Together with down-regulation of Cx43 expression after being treated with TGF-β type I receptor inhibitor Repsox, we deduced that TGF-β1 can positively regulate Cx43 expression in osteocytes. Thus we next focussed on the downstream signals of TGF-β and found that TGF-β1-mediated smads, Smad3 and Smad4, to translocate into nucleus. These translocated signal proteins bind to the promoter of Gja1 which was responsible for the changed expression of Cx43. The present study provides evidence that TGF-β1 can enhance GJIC between osteocytes through up-regulating Cx43 expression and the underlying mechanism involved in the activation of Smad-dependent pathway.

scholarly journals Gene expression in primary cultured astrocytes affected by aluminum: alteration of chaperons involved in protein folding

2010 ◽  
Vol 16 (1) ◽  
pp. 16-24 ◽  
Author(s):  
David A. Aremu ◽  
Ojeiru F. Ezomo ◽  
Shunsuke Meshitsuka
Keyword(s):  
Gene Expression ◽  
Protein Folding ◽  
Cultured Astrocytes ◽  
Primary Cultured Astrocytes
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