title: Evidences of endocytosis via caveolae following blood-brain barrier breakdown by Phoneutria nigriventer spider venom.
abstract: Spider venoms contain neurotoxic peptides aimed at paralyzing prey or for defense against predators; that is why they represent valuable tools for studies in neuroscience field. The present study aimed at identifying the process of internalization that occurs during the increased trafficking of vesicles caused by Phoneutria nigriventer spider venom (PNV)-induced blood-brain barrier (BBB) breakdown. Herein, we found that caveolin-1α is up-regulated in the cerebellar capillaries and Purkinje neurons of PNV-administered P14 (neonate) and 8- to 10-week-old (adult) rats. The white matter and granular layers were regions where caveolin-1α showed major upregulation. The variable age played a role in this effect. Caveolin-1 is the central protein that controls caveolae formation. Caveolar-specialized cholesterol- and sphingolipid-rich membrane sub-domains are involved in endocytosis, transcytosis, mechano-sensing, synapse formation and stabilization, signal transduction, intercellular communication, apoptosis, and various signaling events, including those related to calcium handling. PNV is extremely rich in neurotoxic peptides that affect glutamate handling and interferes with ion channels physiology. We suggest that the PNV-induced BBB opening is associated with a high expression of caveolae frame-forming caveolin-1α, and therefore in the process of internalization and enhanced transcytosis. Caveolin-1α up-regulation in Purkinje neurons could be related to a way of neurons to preserve, restore, and enhance function following PNV-induced excitotoxicity. The findings disclose interesting perspectives for further molecular studies of the interaction between PNV and caveolar specialized membrane domains. It proves PNV to be excellent tool for studies of transcytosis, the most common form of BBB-enhanced permeability.
authors.affiliation: Department of Biochemistry and Tissue Biology, Institute of Biology, State University of Campinas (UNICAMP), 13 083-970 Campinas, São Paulo, Brazil.
authors.forename: Edilene Siqueira
authors.initials: ES
authors.lastname: Soares
authors.affiliation: Department of Biochemistry and Tissue Biology, Institute of Biology, State University of Campinas (UNICAMP), 13 083-970 Campinas, São Paulo, Brazil; Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), 13 083-970 Campinas, São Paulo, Brazil.
authors.forename: Monique Culturato Padilha
authors.initials: MC
authors.lastname: Mendonça
authors.affiliation: Faculty of Technology of Sorocaba, State Center of Paula Souza Technological Education (CEETPS), 18013-280 Sorocaba, São Paulo, Brazil.
authors.forename: Silvia Pierre
authors.initials: SP
authors.lastname: Irazusta
authors.affiliation: Cell Signaling Laboratory, Faculty of Medical Sciences, State University of Campinas (UNICAMP), 13081-970 Campinas, São Paulo, Brazil.
authors.forename: Andressa
authors.initials: A
authors.lastname: Coope
authors.affiliation: Department of Biochemistry and Tissue Biology, Institute of Biology, State University of Campinas (UNICAMP), 13 083-970 Campinas, São Paulo, Brazil.
authors.forename: Leila Miguel
authors.initials: LM
authors.lastname: Stávale
authors.affiliation: Department of Biochemistry and Tissue Biology, Institute of Biology, State University of Campinas (UNICAMP), 13 083-970 Campinas, São Paulo, Brazil; Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), 13 083-970 Campinas, São Paulo, Brazil. Electronic address: hofling@unicamp.br.
authors.forename: Maria Alice
authors.initials: MA
authors.lastname: da Cruz-Höfling
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects*; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000473:pathology; D021941:Caveolae / Q000187:drug effects*; D051242:Caveolin 1 / Q000096:biosynthesis; D004705:Endocytosis / Q000187:drug effects*; D008297:Male; D009479:Neuropeptides / Q000494:pharmacology*; D009498:Neurotoxins / Q000494:pharmacology*; D011689:Purkinje Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D013111:Spider Venoms / Q000494:pharmacology*; D013112:Spiders
chemical_list: C495537:Cav1 protein, rat; D051242:Caveolin 1; D009479:Neuropeptides; D009498:Neurotoxins; D013111:Spider Venoms; C064022:Tx1 neurotoxin
keywords: BBB; Caveolin-1; Endocytosis; Lipid rafts; Transcellular trafficking