Abstract
The family of muscarinic acetylcholine receptors (mAChRs) consists of five members in mammals, encoded by the CHRM1-5 genes. The mAChRs are G-protein-coupled receptors, which can be divided into the following two subfamilies: M2 and M4 receptors coupling to Gi/o; and M1, M3, and M5 receptors coupling to Gq/11. However, despite the fundamental roles played by these receptors, their evolution in vertebrates has not yet been fully described. We have combined sequence-based phylogenetic analyses with comparisons of exon–intron organization and conserved synteny in order to deduce the evolution of the mAChR receptors. Our analyses verify the existence of two ancestral genes prior to the two vertebrate tetraploidizations (1R and 2R). After these events, one gene had duplicated, resulting in CHRM2 and CHRM4; and the other had triplicated, forming the CHRM1, CHRM3, and CHRM5 subfamily. All five genes are still present in all vertebrate groups investigated except the CHRM1 gene, which has not been identified in some of the teleosts or in chicken or any other birds. Interestingly, the third tetraploidization (3R) that took place in the teleost predecessor resulted in duplicates of all five mAChR genes of which all 10 are present in zebrafish. One of the copies of the CHRM2 and CHRM3 genes and both CHRM4 copies have gained introns in teleosts. Not a single separate (nontetraploidization) duplicate has been identified in any vertebrate species. These results clarify the evolution of the vertebrate mAChR family and reveal a doubled repertoire in zebrafish, inviting studies of gene neofunctionalization and subfunctionalization.
Highlights
The muscarinic acetylcholine receptors are G-protein-coupled receptors (GPCRs) involved in a variety of CNS processes such as cognition, learning, and memory
One eNeuro.org reason for this is that IL3 located between TM5 and TM6 is highly variable between receptor subtypes as well as between species for each subtype (Fig. 1-1)
The combined results of these analyses show that the muscarinic acetylcholine receptors (mAChRs) family expanded from two ancestral genes present in the vertebrate predecessor to five mAChR genes in an early vertebrate ancestor, as a result of the 1R and 2R tetraploidization events (Fig. 5)
Summary
The muscarinic acetylcholine receptors (mAChRs) are G-protein-coupled receptors (GPCRs) involved in a variety of CNS processes such as cognition, learning, and memory. They are present in the peripheral nervous system and smooth muscle tissue. The mAChR family consists of five different receptor subtypes named M1– M5, which are encoded by the CHRM1-5 genes. The. Received August 27, 2018; accepted October 17, 2018; First published October 24, 2018. The authors declare no competing financial interests J.E.P. and C.A.B. performed research; J.E.P., C.A.B., and D.L. analyzed data; J.E.P. and D.L. wrote the paper
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