Hericerin derivatives activates a pan-neurotrophic pathway in central hippocampal neurons converging to ERK1/2 signaling enhancing spatial memory.

The traditional medicinal mushroom Hericium erinaceus is known for enhancing peripheral nerve regeneration through targeting nerve growth factor (NGF) neurotrophic activity. Here, we purified and identified biologically new active compounds from H. erinaceus, based on their ability to promote neurite outgrowth in hippocampal neurons. N-de phenylethyl isohericerin (NDPIH), an isoindoline compound from this mushroom, together with its hydrophobic derivative hericene A, were highly potent in promoting extensive axon outgrowth and neurite branching in cultured hippocampal neurons even in the absence of serum, demonstrating potent neurotrophic activity. Pharmacological inhibition of tropomyosin receptor kinase B (TrkB) by ANA-12 only partly prevented the NDPIH-induced neurotrophic activity, suggesting a potential link with BDNF signaling. However, we found that NDPIH activated ERK1/2 signaling in the absence of TrkB in HEK-293T cells, an effect that was not sensitive to ANA-12 in the presence of TrkB. Our results demonstrate that NDPIH acts via a complementary neurotrophic pathway independent of TrkB with converging downstream ERK1/2 activation. Mice fed with H. erinaceus crude extract and hericene A also exhibited increased neurotrophin expression and downstream signaling, resulting in significantly enhanced hippocampal memory. Hericene A therefore acts through a novel pan-neurotrophic signaling pathway, leading to improved cognitive performance.

High-affinity TrkA and p75 neurotrophin receptor complexes: A twisted affair.

Neurotrophin signaling is essential for normal nervous system development and adult function. Neurotrophins are secreted proteins that signal via interacting with two neurotrophin receptor types: the multifaceted p75 neurotrophin receptor and the tropomyosin receptor kinase receptors. In vivo, neurons compete for the limited quantities of neurotrophins, a process that underpins neural plasticity, axonal targeting, and ultimately survival of the neuron. Thirty years ago, it was discovered that p75 neurotrophin receptor and tropomyosin receptor kinase A form a complex and mediate high-affinity ligand binding and survival signaling; however, despite decades of functional and structural research, the mechanism of modulation that yields this high-affinity complex remains unclear. Understanding the structure and mechanism of high-affinity receptor generation will allow development of pharmaceuticals to modulate this function for treatment of the many nervous system disorders in which altered neurotrophin expression or signaling plays a causative or contributory role. Here we re-examine the key older literature and integrate it with more recent studies on the topic of how these two receptors interact. We also identify key outstanding questions and propose a model of inside-out allosteric modulation to assist in resolving the elusive high-affinity mechanism and complex.

Fast-Trk(B)ing the mechanism of antidepressants.

The mechanism by which antidepressants elicit clinical improvements has proven elusive. In a recent publication in Cell, Casarotto et al. (2021) reveal a surprising direct interaction between antidepressants and TrkB. This link provides an important mechanistic insight into synaptic remodeling that may assist in the design of improved antidepressant therapeutics.

Complement C3a receptor modulates embryonic neural progenitor cell proliferation and cognitive performance.

The complement system of innate immunity is emerging as a novel player in neurodevelopmental processes. The receptor for C3a, C3aR, shares a close evolutionary and functional relationship with C5a receptors. Whilst the C5a receptor, C5aR1, has been demonstrated to promote embryonic neural stem cell proliferation, little is known about the role of C3aR in this process. Here we show that C3aR is expressed in a similar manner to C5aR1 in mice, at the apical pole of the embryonic ventricular zone, though it has an opposing function. Using in utero delivery of C3aR agonist and antagonist compounds to the embryonic ventricle, we demonstrate that C3aR functions to decrease proliferation of apical neural progenitor cells (NPC). Intriguingly, C3aR-/- animals also have altered NPC proliferation, but demonstrate an opposing phenotype to animals subjected to pharmacological blockade of C3aR. Finally, despite a grossly normal development of C3aR-/- animals, cognitive behavioural testing of adult mice showed subtle deficits in recall memory. These data demonstrate that in addition to C5a, C3a also has a critical role in the normal development of the mammalian brain.

BRET-based assay to monitor EGFR transactivation by the AT1R reveals Gq/11 protein-independent activation and AT1R-EGFR complexes.

The type 1 angiotensin II (AngII) receptor (AT1R) transactivates the epidermal growth factor receptor (EGFR), which leads to pathological remodeling of heart, blood vessels and kidney. End-point assays are used as surrogates of EGFR activation, however these downstream readouts are not applicable to live cells, in real-time. Herein, we report the use of a bioluminescence resonance energy transfer (BRET)-based assay to assess recruitment of the EGFR adaptor protein, growth factor receptor-bound protein 2 (Grb2), to the EGFR. In a variety of cell lines, both epidermal growth factor (EGF) and AngII stimulated Grb2 recruitment to EGFR. The BRET assay was used to screen a panel of 9 G protein-coupled receptors (GPCRs) and further developed for other EGFR family members (HER2 and HER3); the AT1R was able to transactivate HER2, but not HER3. Mechanistically, AT1R-mediated ERK1/2 activation was dependent on Gq/11 and EGFR tyrosine kinase activity, whereas the recruitment of Grb2 to the EGFR was independent of Gq/11 and only partially dependent on EGFR tyrosine kinase activity. This Gq/11 independence of EGFR transactivation was confirmed using AT1R mutants and in CRISPR cell lines lacking Gq/11. EGFR transactivation was also apparently independent of ß-arrestins. Finally, we used additional BRET-based assays and confocal microscopy to provide evidence that both AngII- and EGF-stimulation promoted AT1R-EGFR heteromerization. In summary, we report an alternative approach to monitoring AT1R-EGFR transactivation in live cells, which provides a more direct and proximal view of this process, including the potential for complexes between the AT1R and EGFR.