Molecular Diversity and Functional Implications of Mammalian Choline Acetyltransferases in Neuronal and Non-Neuronal Cells

Acetylcholine (ACh) is the first identified neurotransmitter and an evolutionarily conserved signaling molecule. Although its role in classical synaptic transmission within the central and peripheral nervous systems has been extensively studied, growing evidence indicates that cholinergic signaling extends beyond neuronal synapses and operates in a broad range of non-neuronal cells. Thus, the cholinergic system represents a complex and widely distributed signaling network with both neuronal and non-neuronal components. Within the nervous system, cholinergic neurons display marked molecular heterogeneity, largely driven by the genomic organization and alternative splicing of the choline acetyltransferase (ChAT) gene. Distinct ChAT mRNA splice variants contribute to region- and cell-type specific cholinergic phenotypes in central and peripheral neurons, including the enteric nervous system, which exemplifies a highly autonomous peripheral cholinergic network. Beyond the nervous system, non-neuronal cholinergic signaling has been identified in epithelial, cardiac, immune, and other cell types, where ACh acts as an autocrine and paracrine regulator of key physiological processes. This review summarizes current knowledge on ACh biosynthesis, focusing on ChAT and its splice variants as molecular determinants of cholinergic diversity and function across neuronal and non-neuronal contexts.