ether a go go potassium channels

Summary

Summary: A family of voltage-gated potassium channels that are characterized by long N-terminal and C-terminal intracellular tails. They are named from the Drosophila protein whose mutation causes abnormal leg shaking under ether anesthesia. Their activation kinetics are dependent on extracellular MAGNESIUM and PROTON concentration.

Top Publications

  1. Choveau F, El Harchi A, Rodriguez N, Louérat Oriou B, Baró I, Demolombe S, et al. Transfer of rolf S3-S4 linker to HERG eliminates activation gating but spares inactivation. Biophys J. 2009;97:1323-34 pubmed publisher
    ..This chimera allows determining the mechanism of action of hERG blockers, as exemplified by the test on ketoconazole. ..
  2. Clancy S, Chen B, Bertaso F, Mamet J, Jegla T. KCNE1 and KCNE3 beta-subunits regulate membrane surface expression of Kv12.2 K(+) channels in vitro and form a tripartite complex in vivo. PLoS ONE. 2009;4:e6330 pubmed publisher
    ..2 channel tripartite complexes. Together these data indicate that KCNE1 and KCNE3 interact directly with Kv12.2 channels to regulate channel membrane trafficking. ..
  3. Zhao J, Hill A, Varghese A, Cooper A, Swan H, Laitinen Forsblom P, et al. Not all hERG pore domain mutations have a severe phenotype: G584S has an inactivation gating defect with mild phenotype compared to G572S, which has a dominant negative trafficking defect and a severe phenotype. J Cardiovasc Electrophysiol. 2009;20:923-30 pubmed publisher
    ..Further investigation, involving a larger number of cohorts, to test the hypothesis that in vitro phenotyping of the intrinsic severity of a given mutation will assist with risk stratification is therefore warranted. ..
  4. McPate M, Zhang H, Adeniran I, Cordeiro J, Witchel H, Hancox J. Comparative effects of the short QT N588K mutation at 37 degrees C on hERG K+ channel current during ventricular, Purkinje fibre and atrial action potentials: an action potential clamp study. J Physiol Pharmacol. 2009;60:23-41 pubmed
    ..Changes in the timing of outward I(hERG) transients elicited by premature stimuli following AP commands indicate that SQT1 may alter the protection that hERG provides cardiac tissue against premature arrhythmogenic stimuli. ..
  5. Miyake A, Takahashi S, Nakamura Y, Inamura K, Matsumoto S, Mochizuki S, et al. Disruption of the ether-a-go-go K+ channel gene BEC1/KCNH3 enhances cognitive function. J Neurosci. 2009;29:14637-45 pubmed publisher
    ..The results indicate that BEC1 may represent the first K+ channel that contributes preferentially and bidirectionally to cognitive function. ..
  6. Hardman R, Forsythe I. Ether-à-go-go-related gene K+ channels contribute to threshold excitability of mouse auditory brainstem neurons. J Physiol. 2009;587:2487-97 pubmed publisher
    ..These ERG currents suggest a potential link between auditory hyperexcitability and acoustic startle triggering of cardiac events in familial LQT2. ..
  7. Huffaker S, Chen J, Nicodemus K, Sambataro F, Yang F, Mattay V, et al. A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia. Nat Med. 2009;15:509-18 pubmed publisher
    ..These results identify a previously undescribed KCNH2 channel isoform involved in cortical physiology, cognition and psychosis, providing a potential new therapeutic drug target. ..
  8. Gu D, Li X, Qi Z, Shi S, Hu M, Liu D, et al. Blockade of HERG K+ channel by isoquinoline alkaloid neferine in the stable transfected HEK293 cells. Naunyn Schmiedebergs Arch Pharmacol. 2009;380:143-51 pubmed publisher
    ..Nef has no effect on the generation and trafficking of HERG protein. A blocked-off HERG channel was one mechanism of the anti-arrhythmic effects by Nef. ..
  9. Elliott D, Dondas N, Munsey T, Sivaprasadarao A. Movement of the S4 segment in the hERG potassium channel during membrane depolarization. Mol Membr Biol. 2009;26:435-47 pubmed publisher
    ..These data indicate that the extent of S4 movement in hERG is similar to other Kv channels, including the archabacterial KvAP and the Shaker channel of Drosophila. ..

More Information

Publications62

  1. Sanguinetti M. HERG1 channelopathies. Pflugers Arch. 2010;460:265-76 pubmed publisher
    ..In addition, up-regulation of hERG1 channel expression has been demonstrated in specific tumors and has been associated with skeletal muscle atrophy in mice. ..
  2. Brelidze T, Carlson A, Zagotta W. Absence of direct cyclic nucleotide modulation of mEAG1 and hERG1 channels revealed with fluorescence and electrophysiological methods. J Biol Chem. 2009;284:27989-97 pubmed publisher
    ..Further studies are necessary to determine if the CNBD in the EAG family of K(+) channels might harbor a binding site for a ligand yet to be uncovered. ..
  3. Hong H, Park M, Lee B, Jo S. Block of the human ether-a-go-go-related gene (hERG) K+ channel by the antidepressant desipramine. Biochem Biophys Res Commun. 2010;394:536-41 pubmed publisher
    ..These results suggest that desipramine is a blocker of the hERG channels, providing a molecular mechanism for the arrhythmogenic side effects during the clinical administration of desipramine. ..
  4. Greenwood I, Yeung S, Tribe R, Ohya S. Loss of functional K+ channels encoded by ether-à-go-go-related genes in mouse myometrium prior to labour onset. J Physiol. 2009;587:2313-26 pubmed publisher
    ..This study provides the first evidence for a regulation of ERG-encoded K(+) channels as a precursor to late pregnancy physiological activity. ..
  5. Ducroq J, Moha Ou Maati H, Guilbot S, Dilly S, Laemmel E, Pons Himbert C, et al. Dexrazoxane protects the heart from acute doxorubicin-induced QT prolongation: a key role for I(Ks). Br J Pharmacol. 2010;159:93-101 pubmed publisher
    ..This effect was prevented by dexrazoxane. This result is important because it illustrates the danger of neglecting I(Ks) in favour of hERG screening alone, for early preclinical testing for possible induction of torsade de pointes. ..
  6. Ziv O, Morales E, Song Y, Peng X, Odening K, Buxton A, et al. Origin of complex behaviour of spatially discordant alternans in a transgenic rabbit model of type 2 long QT syndrome. J Physiol. 2009;587:4661-80 pubmed publisher
    ..In conclusion, tissue heterogeneity plays a significant role in providing substrate for ventricular arrhythmia in LQT2 rabbits by facilitating DA onset and contributing to unstable nodal lines prone to reentry formation. ..
  7. Guo J, Massaeli H, Xu J, Jia Z, Wigle J, Mesaeli N, et al. Extracellular K+ concentration controls cell surface density of IKr in rabbit hearts and of the HERG channel in human cell lines. J Clin Invest. 2009;119:2745-57 pubmed publisher
    ..Because hypokalemia is known to exacerbate long QT syndrome (LQTS) and Torsades de pointes tachyarrhythmias, our findings provide a potential mechanistic link between hypokalemia and LQTS. ..
  8. Pollard C, Abi Gerges N, Bridgland Taylor M, Easter A, Hammond T, Valentin J. An introduction to QT interval prolongation and non-clinical approaches to assessing and reducing risk. Br J Pharmacol. 2010;159:12-21 pubmed publisher
    ..The non-clinical data are essential to inform decisions about compound progression and to optimize the design of clinical QT studies. ..
  9. Shamovsky I, de Graaf C, Alderin L, Bengtsson M, Bladh H, Börjesson L, et al. Increasing selectivity of CC chemokine receptor 8 antagonists by engineering nondesolvation related interactions with the intended and off-target binding sites. J Med Chem. 2009;52:7706-23 pubmed publisher
    ..Electrophysiological measurements and site-directed mutagenesis studies indicated that the repulsive interactions of these fragments with hERG are caused by steric hindrances with residue F656. ..
  10. Larsen A, Olesen S. Differential expression of hERG1 channel isoforms reproduces properties of native I(Kr) and modulates cardiac action potential characteristics. PLoS ONE. 2010;5:e9021 pubmed publisher
    ..Importantly, our results suggest that regional differences in the relative abundance of ERG1 isoforms may represent a potential mechanism underlying the heterogeneity of both APD and APD restitution observed in mammalian hearts. ..
  11. Kise H, Nakamura Y, Hoshiai M, Sugiyama H, Sugita K, Sugiyama A. Cardiac and haemodynamic effects of tacrolimus in the halothane-anaesthetized dog. Basic Clin Pharmacol Toxicol. 2010;106:288-95 pubmed publisher
    ..Moreover, the monitoring of the actual drug concentration may not necessarily reflect its effects on the cardiovascular system; thus, frequent monitoring of cardiovascular variables may be essential for tacrolimus-treated patients. ..
  12. Wu L, Rajamani S, Li H, January C, Shryock J, Belardinelli L. Reduction of repolarization reserve unmasks the proarrhythmic role of endogenous late Na(+) current in the heart. Am J Physiol Heart Circ Physiol. 2009;297:H1048-57 pubmed publisher
    ..Inhibition of this current partially reverses MAPD prolongation and abolishes arrhythmic activity caused by I(K) inhibitors...
  13. Palmer A, Chiesa V, Schmid A, Münch G, Grobbel B, Zimmermann P, et al. Tetrahydrochromenoimidazoles as potassium-competitive acid blockers (P-CABs): structure-activity relationship of their antisecretory properties and their affinity toward the hERG channel. J Med Chem. 2010;53:3645-74 pubmed publisher
    ..Several tetrahydrochromenoimidazoles were identified that possessed a comparable profile as the candidate 4. ..
  14. Ogawa K, Nakamura Y, Terano K, Ando T, Hishitani T, Hoshino K. Isolated non-compaction of the ventricular myocardium associated with long QT syndrome: a report of 2 cases. Circ J. 2009;73:2169-72 pubmed
    ..Both cases had the KCNH2 mutation. To the best of our knowledge, this is the first report investigating INCVM with LQTS. ..
  15. Ponte M, Keller G, Di Girolamo G. Mechanisms of drug induced QT interval prolongation. Curr Drug Saf. 2010;5:44-53 pubmed
    ..Several drugs had been subject of withdrawal because QT-prolongation and arrhythmia. Understanding of processes involved in drug-induced QT prolongation is needed for the study and prevention of life-threatening arrhythmias. ..
  16. Alvarez P, Pahissa J. QT alterations in psychopharmacology: proven candidates and suspects. Curr Drug Saf. 2010;5:97-104 pubmed
    ..Careful selection of the psychotropic and identification of patient's risk factors for QTc prolongation is applicable in current clinical practice. ..
  17. Keller G, Ponte M, Di Girolamo G. Other drugs acting on nervous system associated with QT-interval prolongation. Curr Drug Saf. 2010;5:105-11 pubmed
  18. Grunnet M. Repolarization of the cardiac action potential. Does an increase in repolarization capacity constitute a new anti-arrhythmic principle?. Acta Physiol (Oxf). 2010;198 Suppl 676:1-48 pubmed publisher
    ..Experimental evidence from in vitro, ex vivo and in vivo settings will be included. Furthermore, conceptual differences between the short QT syndrome and I(Kr) activation will be accounted for. ..
  19. Chen J, Chen K, Sroubek J, Wu Z, Thomas D, Bian J, et al. Post-transcriptional control of human ether-a-go-go-related gene potassium channel protein by alpha-adrenergic receptor stimulation. Mol Pharmacol. 2010;78:186-97 pubmed publisher
    ..These findings show that alpha1A-AR stimulation is capable of influencing the balance of HERG channel synthesis and degradation via multiple signaling pathways, a process that may have relevance in cardiac diseases and treatment. ..
  20. Chui R, Fosdick A, Conner R, Jiang J, Bruenner B, Vargas H. Assessment of two external telemetry systems (PhysioJacket and JET) in beagle dogs with telemetry implants. J Pharmacol Toxicol Methods. 2009;60:58-68 pubmed publisher
    ..As such, this method is an invaluable tool for obtaining high quality ECG data from repeat-dose toxicology studies. ..
  21. Robertson G. Endocytic control of ion channel density as a target for cardiovascular disease. J Clin Invest. 2009;119:2531-4 pubmed publisher
  22. Kobayashi K, Uchiyama M, Ito H, Takahashi H, Yoshizumi T, Sakoh H, et al. Discovery of novel arylpyrazole series as potent and selective opioid receptor-like 1 (ORL1) antagonists. Bioorg Med Chem Lett. 2009;19:3627-31 pubmed publisher
  23. Wang Q, Wang X, Chen X, Yu J, Wang J, Sun J, et al. Genetic polymorphism of KCNH2 confers predisposition of acquired atrial fibrillation in Chinese. J Cardiovasc Electrophysiol. 2009;20:1158-62 pubmed publisher
    ..Further genetic and functional studies are required to identify the etiological variants in linkage disequilibrium with this polymorphism. ..
  24. Berglund S, Egner B, Gradén H, Gradén J, Morgan D, Inghardt T, et al. Optimization of piperidin-4-yl-urea-containing melanin-concentrating hormone receptor 1 (MCH-R1) antagonists: Reducing hERG-associated liabilities. Bioorg Med Chem Lett. 2009;19:4274-9 pubmed publisher
    ..Different strategies to increase hERG selectivity were implemented and resulted in the identification of piperidin-4-yl-urea compounds as potent MCH-R1 antagonists with minimized hERG inhibition. ..
  25. Stary A, Wacker S, Boukharta L, Zachariae U, Karimi Nejad Y, Aqvist J, et al. Toward a consensus model of the HERG potassium channel. ChemMedChem. 2010;5:455-67 pubmed publisher
    ..Kuyucak, P. W. Kuchel, J. I. Vandenberg, J. Biol. Chem. 2009, 284, 1000-1008). We expect the modeled structure to be useful as a basis both for computational studies of channel function and kinetics as well as the design of experiments. ..
  26. Zhao Y, Cui C, Li Y, Huang C. [Eukaryotic expression vector pcDNA3-HERG transfection inhibits angiotensin II induced neonatal rabbit ventricular myocyte hypertrophy in vitro]. Zhonghua Xin Xue Guan Bing Za Zhi. 2009;37:931-5 pubmed
    ..Ang II induced prolongation of APD(90) is directly associated with myocyte hypertrophy by increasing the Ca(2+) influx and resulting in the increment of intracellular Ca(2+) and activation of CaN reaction pathway. ..
  27. Redaelli E, Cassulini R, Silva D, Clement H, Schiavon E, Zamudio F, et al. Target promiscuity and heterogeneous effects of tarantula venom peptides affecting Na+ and K+ ion channels. J Biol Chem. 2010;285:4130-42 pubmed publisher
    ..Our observations could also aid in future structure-function studies and might help the development of novel ion channel-specific drugs. ..
  28. Rodriguez N, Amarouch M, Montnach J, Piron J, Labro A, Charpentier F, et al. Phosphatidylinositol-4,5-bisphosphate (PIP(2)) stabilizes the open pore conformation of the Kv11.1 (hERG) channel. Biophys J. 2010;99:1110-8 pubmed publisher
    ..From the physiological aspect, we established that the sensitivity of hERG to PIP(2) comes close to that of KCNE1-KCNQ1 channels, which lies in the range of physiological PIP(2) variations. ..
  29. Omichi C, Momose Y, Kitahara S. Congenital long QT syndrome presenting with a history of epilepsy: misdiagnosis or relationship between channelopathies of the heart and brain?. Epilepsia. 2010;51:289-92 pubmed publisher
    ..Epilepsy, a disorder of neural function, is also associated with abnormal channel function. The possibility that some channelopathies can manifest as both LQTS and epilepsy is discussed. ..
  30. Hirdes W, Napp N, Wulfsen I, Schweizer M, Schwarz J, Bauer C. Erg K+ currents modulate excitability in mouse mitral/tufted neurons. Pflugers Arch. 2009;459:55-70 pubmed publisher
    ..A pharmacological block of erg channels depolarized the resting potential of M/T cells and clearly demonstrated the involvement of erg channels in the control of mitral cell excitability. ..
  31. Gleeson P, Bravi G, Modi S, Lowe D. ADMET rules of thumb II: A comparison of the effects of common substituents on a range of ADMET parameters. Bioorg Med Chem. 2009;17:5906-19 pubmed publisher
    ..We also relate the change in activity observed for each substituent to differences in their molecular properties in an effort to identify any structural alerts. ..
  32. Mitchell H, Dankulich W, Hartman G, Prueksaritanont T, Schmidt A, Vogel R, et al. Design, synthesis, and biological evaluation of 16-substituted 4-azasteroids as tissue-selective androgen receptor modulators (SARMs). J Med Chem. 2009;52:4578-81 pubmed publisher
    ..On the basis of its in vitro profile, 21 was evaluated in the OVX and ORX rat models and exhibited an osteoanabolic, tissue-selective profile. ..
  33. Zhang X, Bursulaya B, Lee C, Chen B, Pivaroff K, Jegla T. Divalent cations slow activation of EAG family K+ channels through direct binding to S4. Biophys J. 2009;97:110-20 pubmed publisher
    ..2 match these constraints. Our results suggest close conformational conservation between closed EAG and Shaker family channels, despite large differences in voltage sensitivity, activation rates, and activation thresholds...
  34. Noma K, Kimura K, Minatohara K, Nakashima H, Nagao Y, Mizoguchi A, et al. Triple N-glycosylation in the long S5-P loop regulates the activation and trafficking of the Kv12.2 potassium channel. J Biol Chem. 2009;284:33139-50 pubmed publisher
    ..Furthermore, we could not detect unglycosylated channels in the mouse brain. Our data suggest that only glycosylated Kv12.2 channels show proper voltage dependence and are utilized in vivo. ..
  35. Dolderer J, Schuldes H, Bockhorn H, Altmannsberger M, Lambers C, von Zabern D, et al. HERG1 gene expression as a specific tumor marker in colorectal tissues. Eur J Surg Oncol. 2010;36:72-7 pubmed publisher
    ..Our data indicate that HERG1, but not CEA, CK19 or CK20, is a highly sensitive and reliable tumor biomarker that may constitute a novel molecular target for tumor treatment. ..
  36. Yao Y, Teng S, Li N, Zhang Y, Boyden P, Pu J. Aminoglycoside antibiotics restore functional expression of truncated HERG channels produced by nonsense mutations. Heart Rhythm. 2009;6:553-60 pubmed publisher
    ..2-fold (n = 12, P <.05). The study findings provide proof of principle that interventions designed to read through premature stop mutations may at least partially reverse the LQT2 phenotype in vitro. ..
  37. Porthan K, Marjamaa A, Viitasalo M, Vaananen H, Jula A, Toivonen L, et al. Relationship of common candidate gene variants to electrocardiographic T-wave peak to T-wave end interval and T-wave morphology parameters. Heart Rhythm. 2010;7:898-903 pubmed publisher
    ..The previously observed prognostic value of T-wave morphology parameters likely is not based on these SNPs. ..
  38. Karczewski J, Wang J, Kane S, Kiss L, Koblan K, Culberson J, et al. Analogs of MK-499 are differentially affected by a mutation in the S6 domain of the hERG K+ channel. Biochem Pharmacol. 2009;77:1602-11 pubmed publisher
    ..Together these data suggest that interaction with Phe656 is not an absolute requirement for the binding of all methanesulfonanilide compounds, and that this residue may play a broader role in regulating access to the inner vestibule. ..
  39. Towart R, Linders J, Hermans A, Rohrbacher J, van der Linde H, Ercken M, et al. Blockade of the I(Ks) potassium channel: an overlooked cardiovascular liability in drug safety screening?. J Pharmacol Toxicol Methods. 2009;60:1-10 pubmed publisher
    ..et al. (2008) Predicting drug-induced changes in QT interval and arrhythmias: QT-shortening drugs point to gaps in the ICH S7B Guidelines. British Journal of Pharmacology, 154, 1427-1438] in the ICH S7B regulatory guidelines. ..
  40. Zhang X, Bertaso F, Yoo J, Baumgärtel K, Clancy S, Lee V, et al. Deletion of the potassium channel Kv12.2 causes hippocampal hyperexcitability and epilepsy. Nat Neurosci. 2010;13:1056-8 pubmed publisher
    ..Kv12.2-/- (also known as Kcnh3-/-) mice showed signs of persistent neuronal hyperexcitability including frequent interictal spiking, spontaneous seizures and increased sensitivity to the chemoconvulsant pentylenetetrazol. ..
  41. Rihel J, Prober D, Arvanites A, Lam K, Zimmerman S, Jang S, et al. Zebrafish behavioral profiling links drugs to biological targets and rest/wake regulation. Science. 2010;327:348-51 pubmed publisher
    ..These results demonstrate the power of high-throughput behavioral profiling in zebrafish to discover and characterize psychotropic drugs and to dissect the pharmacology of complex behaviors. ..
  42. Keller D, Grenier J, Christé G, Dubouloz F, Osswald S, Brink M, et al. Characterization of novel KCNH2 mutations in type 2 long QT syndrome manifesting as seizures. Can J Cardiol. 2009;25:455-62 pubmed
    ..Triggers for life-threatening arrhythmias in LQTS2 are often auditory stimuli...
  43. Doddareddy M, Klaasse E, Shagufta -, Ijzerman A, Bender A. Prospective validation of a comprehensive in silico hERG model and its applications to commercial compound and drug databases. ChemMedChem. 2010;5:716-29 pubmed publisher
  44. Weissenburger J, Funck Brentano C, Jaillon P, Charbit B. Droperidol and ondansetron in vitro electrophysiological drug interaction study. Fundam Clin Pharmacol. 2009;23:719-26 pubmed publisher
    ..Combination of ondansetron and droperidol exhibits an additive effect on AP duration. However, within clinically relevant concentrations, ondansetron does not further increase the AP prolongation caused by droperidol alone. ..
  45. Mélykúti B, Burrage K, Zygalakis K. Fast stochastic simulation of biochemical reaction systems by alternative formulations of the chemical Langevin equation. J Chem Phys. 2010;132:164109 pubmed publisher
    ..We illustrate our findings by considering alternative formulations of the CLE for a human ether a-go-go related gene ion channel model and the Goldbeter-Koshland switch. ..
  46. Massaeli H, Sun T, Li X, Shallow H, Wu J, Xu J, et al. Involvement of caveolin in low K+-induced endocytic degradation of cell-surface human ether-a-go-go-related gene (hERG) channels. J Biol Chem. 2010;285:27259-64 pubmed publisher
    ..Our data indicate that a caveolin-dependent endocytic route is involved in low K(+)(o)-induced degradation of mature hERG channels. ..
  47. Pages G, Torres A, Ju P, Bansal P, Alewood P, Kuchel P, et al. Structure of the pore-helix of the hERG K(+) channel. Eur Biophys J. 2009;39:111-20 pubmed publisher
  48. Hirdes W, Dinu C, Bauer C, Boehm U, Schwarz J. Gonadotropin-releasing hormone inhibits ether-à-go-go-related gene K+ currents in mouse gonadotropes. Endocrinology. 2010;151:1079-88 pubmed publisher
    ..In addition, the erg channels are modulated by GnRH by an as-yet unknown signal cascade...
  49. Zachariae U, Giordanetto F, Leach A. Side chain flexibilities in the human ether-a-go-go related gene potassium channel (hERG) together with matched-pair binding studies suggest a new binding mode for channel blockers. J Med Chem. 2009;52:4266-76 pubmed publisher
    ..The binding model also suggests a molecular mechanism for the link between high-affinity hERG binding and C-type inactivation. ..
  50. Zhao X, Gu D, Qi Z, Chen M, Wei T, Li B, et al. Comparative effects of sophocarpine and sophoridine on hERG K+ channel. Eur J Pharmacol. 2009;607:15-22 pubmed publisher
    ..Sophocarpine may have a higher binding affinity for the inactivate state. In contrast, sophoridine has a higher binding affinity for the open state. Both drugs have no effect on the generation and trafficking of hERG protein. ..
  51. Obrezanova O, Segall M. Gaussian processes for classification: QSAR modeling of ADMET and target activity. J Chem Inf Model. 2010;50:1053-61 pubmed publisher
  52. Raschi E, Ceccarini L, De Ponti F, Recanatini M. hERG-related drug toxicity and models for predicting hERG liability and QT prolongation. Expert Opin Drug Metab Toxicol. 2009;5:1005-21 pubmed publisher
    ..This prediction requires expertise from different areas and should encompass emerging issues such as interference with hERG trafficking and QT shortening. ..
  53. Hunter C, Kadakia T, Cooper D, Perretti M, Schwartz R, Brown S. Selective inhibitors of Kv11.1 regulate IL-6 expression by macrophages in response to TLR/IL-1R ligands. ScientificWorldJournal. 2010;10:1580-96 pubmed publisher
    ..Our data might also explain the altered phenotypes displayed by PECAM-1 knockout mice in several disease models. ..