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Inhibition of Phosphorylation of TrkB and TrkC and Their Signal Transduction by α2‐Macroglobulin

Abstract: Monoamine‐activated α2‐macroglobulin (α2M) was shown to reduce the dopamine concentration in corpus striatum of adult rat brains and inhibit other neuronal functions in vivo and in vitro. As brain‐derived neurotrophic factor, neurotrophin‐4, and neurotrophin‐3 are important neurotrophic factors for dopaminergic neurons, the effect of monoamine‐activated α2M on signal transduction by trkB and trkC was investigated. The results show that monoamine‐activated α2M binds to trkB and inhibits brain‐derived neurotrophic factor/neurotrophin‐4‐promoted autophosphorylation of trkB in a dose‐dependent manner in both trkB‐expressing NIH3T3 (NIH3T3‐trkB) and human neuroblastoma SH‐SY5Y cells. Monoamine‐activated α2M also blocks tyrosine phosphorylation of phospholipase C‐γ1 and extracellular signal‐regulated protein kinase (ERK)‐1, which are key intracellular proteins involved in trkB signal transduction. Similarly, monoamine‐activated α2M inhibits tyrosine phosphorylation of neurotrophin‐3‐induced trkC and its signal transduction in a dose‐dependent manner in NIH3T3 cells expressing trkC (NIH3T3‐trkC). In contrast to monoamine‐activated α2M, normal α2M has little or no significant inhibitory effect on the phosphorylation of trkB and trkC. In addition, the retinoic acid‐promoted tyrosine phosphorylation of phospholipase C‐γ1, ERK‐1, and/or ERK‐2 in SH‐SY5Y cells was unaffected by monoamine‐activated α2M; this suggests that the inhibitory effect of activated α2M on the neurotrophin‐stimulated phosphorylation of intracellular signalling proteins may be specific. Taken together, the data indicate that activated α2M is a pan‐trk inhibitor, which by virtue of its binding to trk receptors may block trk‐mediated signal transduction in dopaminergic neurons and lead to reduction of dopamine concentration in corpus striatum.