Fig. 4.

Summary of studies and new suggested working model of the Q pathway to pMF. A: former working model of the Q pathway to pMF in which G_q-coupled receptors elicit complex downstream signaling. The initiating receptor was initially postulated to signal via PKCθ, leading to new BDNF synthesis with subsequent TrkB receptor activation. Downstream signaling was thought to be dependent on TrkB induced MEK/ERK signaling, ultimately leading to pMF (Baker-Herman et al. 2004; Devinney et al. 2013; Feldman et al. 2003; Mitchell et al. 2001). B: we activated the Q pathway by pharmacologically manipulating key proteins involved in the signaling cascade leading to pMF (BDNF/TrkB). We administered inhibitors that blocked the three canonical TrkB signaling pathways including MEK/ERK, PI3K/Akt, and PLC/PKC (PKCθ), followed by intrathecal BDNF administration to elicit pMF. C: present study demonstrates that PKCθ is the only pathway necessary for BDNF/TrkB induced pMF. Thus our working model of the Q pathway to pMF (A) requires revision; MEK/ERK must be signaling upstream from BDNF/TrkB signaling, whereas PKCθ is a downstream mediator (C).