Fig. 2: Gaps in understanding CHRFAM7A effect on α7 nAChR in the neuronal lineage.

A Schematic diagram illustrating α7 nAChR-mediated signaling cascades in neuronal cells. Agonist binding to the α7 nAChR causes the receptor activation and an increase in Ca²⁺ concentration. Ionotropic receptor function is associated with Ca²⁺ influx from the extracellular space and calcium-induced calcium release (CICR) from the endoplasmic reticulum. The desensitized, inactive receptor is thought to function as a metabotropic receptor activating inositol 1,4,5-trisphosphate (IP₃) induced calcium release (IICR) from the ER. Downstream Ca²⁺ signaling is implicated in 1) neurotransmitter release; 2) structural LTP (depends on sequential activation of Calcium–calmodulin (CaM)-dependent protein kinase II (CaMKII), protein kinase A (PKA), Extracellular signal-regulated kinase (ERK), and cyclic AMP response element binding protein, CREB; 3) activation of Phosphoinositide 3-kinase (PI3K) and Akt that leads to inactivation of glycogen synthase kinase 3 beta (GSK3β), and downregulation of apoptosis through downregulation of BAX and upregulation of Bcl2 that ultimately results in neuroprotection; 4) activation of RhoA that causes a decrease in actin and tubulin polymerization and attenuates neurite outgrowth and microtubule assembly; 5) activation of CDC42 that leads to filopodia membrane specialization in neurite outgrowth, growth cone, and dendritic spine. B CHRFAM7A effect on α7 nAChR-mediated signaling pathways in neurons has been partially elucidated. α7/CHRFAM7A nAChR being a hypomorphic receptor demonstrates decreased activation by electrophysiology and diminished Ca²⁺ influx. The hypomorphic receptor has decreased agonist (α-BTX) binding and mitigates amyloid beta 1-42 (Aβ_1-42) uptake. α7/CHRFAM7A nAChR leads to decreased channel open probability shifting the time spent in CICR to IICR associated with activation of small GTPase Rac1. Downstream, Rac1 switches from CDC42/filopodia to Rac1/lamellipodia membrane structure at all levels of the neuronal unit: neurite outgrowth, growth cone, and dendritic spine. Compared to α7 nAChR (A), α7/CHRFAM7A nAChR associated phenotypes and signaling demonstrate significant gaps in knowledge (B) Dotted lines represent predicted pathways (created with BioRender.com).