Kinin-B2 Receptor Activity Determines the Differentiation Fate of Neural Stem Cells

Autor(es):Mostrar menos -

Trujillo, Cleber A. ^[1] ; Negraes, Priscilla D. ^[1] ; Schwindt, Telma T. ^[1] ; Lameu, Claudiana ^[1] ; Carromeu, Cassiano ^{[2, 3]} ; Muotri, Alysson R. ^{[2, 3]} ; Pesquero, Joao B. ^[4] ; Cerqueira, Debora M. ^[5] ; Pillat, Micheli M. ^[1] ; de Souza, Hellio D. N. ^[1] ; Turaca, Lauro T. ^[4] ; Abreu, Jose G. ^[5] ; Ulrich, Henning ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Quim, Dept Bioquim, BR-05508000 Sao Paulo - Brazil

^[2] Univ Calif San Diego, Dept Pediat, San Diego, CA 92093 - USA

^[3] Univ Calif San Diego, Dept Cellular & Mol Med, San Diego, CA 92093 - USA

^[4] Univ Fed Sao Paulo, Dept Biofis, BR-04023062 Sao Paulo - Brazil

^[5] Univ Fed Rio de Janeiro, Inst Ciencias Biomed, BR-21941902 Rio De Janeiro - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Journal of Biological Chemistry; v. 287, n. 53, p. 44046-44061, DEC 28 2012.
• Citações Web of Science: 24

Resumo

Bradykinin is not only important for inflammation and blood pressure regulation, but also involved in neuromodulation and neuroprotection. Here we describe novel functions for bradykinin and the kinin-B2 receptor (B2BkR) in differentiation of neural stem cells. In the presence of the B2BkR antagonist HOE-140 during rat neurosphere differentiation, neuron-specific beta 3-tubulin and enolase expression was reduced together with an increase in glial protein expression, indicating that bradykinin- induced receptor activity contributes to neurogenesis. In agreement, HOE-140 affected in the same way expression levels of neural markers during neural differentiation of murine P19 and human iPS cells. Kinin-B1 receptor agonists and antagonists did not affect expression levels of neural markers, suggesting that bradykinin-mediated effects are exclusively mediated via B2BkR. Neurogenesis was augmented by bradykinin in the middle and late stages of the differentiation process. Chronic treatment with HOE-140 diminished eNOS and nNOS as well as M1-M4 muscarinic receptor expression and also affected purinergic receptor expression and activity. Neurogenesis, gliogenesis, and neural migration were altered during differentiation of neurospheres isolated from B2BkR knock-out mice. Whole mount in situ hybridization revealed the presence of B2BkR mRNA throughout the nervous system in mouse embryos, and less beta 3-tubulin and more glial proteins were expressed in developing and adult B2BkR knock-out mice brains. As a underlying transcriptional mechanism for neural fate determination, HOE-140 induced up-regulation of Notch1 and Stat3 gene expression. Because pharmacological treatments did not affect cell viability and proliferation, we conclude that bradykinin-induced signaling provides a switch for neural fate determination and specification of neurotransmitter receptor expression. (AU)

• Processo FAPESP: 06/61285-9 - Bases moleculares da diferenciação de células-tronco e progenitoras neurais
• Beneficiário: Alexander Henning Ulrich
• Modalidade de apoio: Auxílio à Pesquisa - Temático