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   selective protection of murine cerebral gi/o-proteins from inactivation by parenterally injected pertussis toxin  
   
نویسنده vega salvador castaneda ,leiss veronika ,piekorz roland ,calaminus carsten ,pexa katja ,vuozzo marta ,schmid andreas m. ,devanathan vasudharani ,kesenheimer christian ,pichler bernd j. ,beer-hammer sandra ,nürnberg bernd
منبع journal of molecular medicine - 2020 - دوره : 98 - شماره : 1 - صفحه:97 -110
چکیده    Pertussis toxin (ptx) is a potent virulence factor in patients suffering from whooping cough, but in its detoxified version, it is applied for vaccination. it is thought to contribute to the pathology of the disease including various cns malfunctions. based on its enzymatic activity, ptx disrupts gpcr-dependent signaling by modifying the α-subunit of heterotrimeric gi/o-proteins. it is also extensively used as a research tool to study neuronal functions in vivo and in vitro. however, data demonstrating the penetration of ptx from the blood into the brain are missing. here, we examined the gαi/o-modifying activity of ptx in murine brains after its parenteral application. ex vivo biodistribution analysis of [124i]-ptx displayed poor distribution to the brain while relatively high concentrations were visible in the pancreas. ptx affected cns and endocrine functions of the pancreas as shown by open-field and glucose tolerance tests, respectively. however, while pancreatic islet gαi/o-proteins were modified, their neuronal counterparts in brain tissue were resistant towards ptx as indicated by different autoradiographic and immunoblot sds-page analyses. in contrast, ptx easily modified brain gαi/o-proteins ex vivo. an attempt to increase bbb permeability by application of hypertonic mannitol did not show ptx activity on neuronal g proteins. consistent with these findings, in vivo mri analysis did not point to an increased blood-brain barrier (bbb) permeability following ptx treatment. our data demonstrate that the cns is protected from ptx. thus, we hypothesize that the bbb hinders ptx to penetrate into the cns and to deliver its enzymatic activity to brain gαi/o-proteins.
کلیدواژه pertussis toxin/ptx ,g-proteins ,biodistribution ,cns ,blood-brain barrier
آدرس eberhard karls university tübingen and university medical center, werner siemens imaging center, department of preclinical imaging and radiopharmacy, germany. eberhard karls university, department of nuclear medicine and clinical molecular imaging, germany, eberhard karls university tübingen, institute for experimental and clinical pharmacology and toxicology, interfaculty center for pharmacogenomics and drug research, department of pharmacology and experimental therapy, germany, heinrich heine university düsseldorf, institute for biochemistry and molecular biology ii, medical faculty, germany, eberhard karls university tübingen and university medical center, werner siemens imaging center, department of preclinical imaging and radiopharmacy, germany, heinrich heine university düsseldorf, institute for biochemistry and molecular biology ii, medical faculty, germany, eberhard karls university tübingen and university medical center, werner siemens imaging center, department of preclinical imaging and radiopharmacy, germany, eberhard karls university tübingen and university medical center, werner siemens imaging center, department of preclinical imaging and radiopharmacy, germany, eberhard karls university tübingen, institute for experimental and clinical pharmacology and toxicology, interfaculty center for pharmacogenomics and drug research, department of pharmacology and experimental therapy, germany. indian institute of science education and research (iiser), neuroscience lab, department of biology, india, eberhard karls university tübingen and university medical center, werner siemens imaging center, department of preclinical imaging and radiopharmacy, germany, eberhard karls university tübingen and university medical center, werner siemens imaging center, department of preclinical imaging and radiopharmacy, germany. eberhard karls university, department of nuclear medicine and clinical molecular imaging, germany, eberhard karls university tübingen, institute for experimental and clinical pharmacology and toxicology, interfaculty center for pharmacogenomics and drug research, department of pharmacology and experimental therapy, germany, eberhard karls university tübingen, institute for experimental and clinical pharmacology and toxicology, interfaculty center for pharmacogenomics and drug research, department of pharmacology and experimental therapy, germany. eberhard karls university tübingen, and university medical center, institute for experimental and clinical pharmacology and toxicology, department of toxicology, germany
 
     
   
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