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Volume 17, Number 21, Issue of November 1, 1997 pp. 8391-8401
Copyright ©1997 Society for Neuroscience

Bradykinin-Induced Collapse of Rat Pheochromocytoma (PC12) Cell Growth Cones: A Role for Tyrosine Kinase Activity

Received Aug. 8, 1997; accepted Aug. 20, 1997.

Benno Schindelholz and Bernhard F. X. Reber

Department of Pharmacology, University of Bern, CH-3010 Bern, Switzerland

Pathfinding of growing nerve processes is guided by extracellular guidance cues. Here we report growth cone collapse of NGF-differentiated PC12 cells in culture evoked by the neuropeptide bradykinin. The growth cone response is mediated by B₂ bradykinin receptors. Two different effects were distinguished. (1) Disappearance of filopodia occurred together with a loss of fibrillar actin (F-actin) in the growth cones at picomolar concentrations of bradykinin. The relative F-actin content was measured by means of rhodamine-phalloidin fluorescence using confocal microscopy. (2) Bradykinin-induced Ca²⁺ release and retraction of the neurite occurred at nanomolar concentrations. Ca²⁺ responses at single growth cones were measured using a 1:1 mixture of fura-red and fluo-3 Ca²⁺-sensitive dyes. The [Ca²⁺]_i rise is not a prerequisite for the observed effects, because F-actin loss and retraction occurred during inhibition of Ca²⁺ responses. In contrast, inhibition by genistein pointed to a tyrosine kinase activity in the bradykinin-evoked cellular events. Subsequent analysis of phosphotyrosine proteins revealed that bradykinin stimulated tyrosine phosphorylation of the cytoskeleton-associated protein paxillin and the nonreceptor protein tyrosine kinase pp60^c-src. Paxillin and pp60^c-src co-precipitated after bradykinin treatment. Immunostaining experiments showed punctate distribution of paxillin along PC12 neurites and in growth cones. Taken together, our data suggest that pp60^c-src and paxillin are putative components of the intracellular signaling pathway of bradykinin-mediated neurite retraction and provide evidence for a crosstalk between G-protein- and tyrosine kinase-dependent pathways in these cellular events.

Key words: pheochromocytoma cell; growth cone collapse; F-actin; bradykinin; calcium; pp60^c-src; tyrosine kinase; paxillin

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