Calcium influx through muscle nAChR-channels: One route, multiple roles

Although Ca²⁺ influx through muscle nAChR-channels has been described over the past 40 years, its functions remain still poorly understood. In this review we suggest possible roles of Ca²⁺ entry at all stages of muscle development, summarizing the evidence present in literature. nAChRs are expressed in myoblasts prior to fusion, and can be activated in the absence of an ACh-releasing nerve terminal, with Ca²⁺ influx likely contributing to regulate cell fusion. Upon establishment of nerve-muscle contact, Ca²⁺ influx contributes to orchestrate the signaling required for the correct formation of the neuromuscular junction. Finally, in the mature synapse, Ca²⁺ entry through postsynaptic nAChR-channels - highly Ca²⁺ permeable, in particular in humans - acts on K⁺ and Na⁺ channels to shape endplate excitability. However, when genetic defects cause excessive channel activation, Ca²⁺ influx becomes toxic and causes endplate myopathy. Throughout the review, we highlight how Ricardo Miledi has contributed to construct this whole body of knowledge, from the initial description of Ca²⁺ permeability of endplate nAChR channels, to the rationale for the treatment of endplate excitotoxic damage under pathological conditions. This article is part of a Special Issue entitled: SI: Honoring Ricardo Miledi - outstanding neuroscientist of XX-XXI centuries.