Adaptation of the endplate in skeletal muscle of Homer 2 −/− mice

: At the neuromuscular junction, nicotinic acetylcholine receptor (nAChR) dynamics are regulated in a nerve- and activity-dependent manner. Correlated local alterations in myoplasmic [Ca2+]i, induced by IP3-sensitive subsynaptic Ca2+ stores, have been proposed to signal motor endplate adaptation to motor neuron stimulation. Accordingly, there is evidence for a modulatory role of Ca2+/calmodulin-dependent protein kinase IIβ (CaMKIIβ) in the sorting, targeting, and/or incorporation of nAChRs into the postsynaptic membrane. As the scaffold protein Homer 2 emerges as a key player in integrating downstream postsynaptic signaling pathways, this study investigated the possible involvement of Homer 2 in the molecular mechanism controlling nAChR dynamics. Using Homer 2-/- transgenic mice, it was found that Homer 2 ablation leads to a chronic adaptation of the endplate characterized by: 1) reduction in nAChR activity due to slower insertion of nAChRs into the endplate; 2) reduced subsynaptic IP3R1 content and IP3-releasable Ca2+; and 3) impaired colocalization of CaMKIIβ with nAChRs. Overall, the present results demonstrate that Homer 2 ablation produces a significant alteration in endplate nAChR dynamics, which is associated with impaired organization of the subsynaptic IP3-driven Ca2+ signaling mechanism.NEW & NOTEWORTHY This research sheds light on the role of Homer 2 in organizing the subsynaptic microdomain, where nAChRs, IP3R1s, and CaMKIIβ assemble to regulate nAChR dynamics. The present results point to a novel type of endplate instability, which may have implications for understanding neuromuscular junction function and related disorders.