TrkC has distinct spatiotemporal dynamics compared to TrkA and TrkB

Abstract

Neurotrophins are critical regulators of neuronal development and have been implicated as therapeutic targets in a range of neurodegenerative and psychiatric disorders. Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4) signal through the receptor tyrosine kinase family of tropomyosin receptor kinase (Trk) receptors. These include TrkA responding to canonical ligand NGF, TrkB responding to BDNF or NT-4, and TrkC responding to NT-3. While TrkA and TrkB have been comparatively well studied, the fundamental pharmacological properties of TrkC remain largely unexplored. Here, we developed and utilised real-time bioluminescence- or fluorescence-based resonance energy transfer (BRET or FRET) biosensors to study the real-time spatial and temporal dynamics at 37{degrees}C to profile Trk receptor dimerisation, trafficking and nuclear ERK signalling in response to neurotrophin stimulation. TrkA and TrkB displayed consistent concentration-dependent dimerisation, trafficking, and signalling. TrkC, on the other hand, exhibited considerable dimerisation but reduced trafficking and ERK signalling relative to TrkA or TrkB. There was also evidence for comparable activation by both canonical and some non-canonical ligands across the Trk family in response to NGF, BDNF, NT-3, or NT-4 across signalling and trafficking assays. The divergence between robust receptor oligomerisation and minimal trafficking suggests TrkC is subject to unique molecular mechanisms distinct from TrkA or TrkB.