Evolution of New Hormone Function: Loss and Gain of a Receptor

Abstract

The vertebrate proglucagon gene encodes three glucagon-like sequences (glucagon, glucagon-like peptide-1 [GLP-1], and glucagon-like peptide 2 [GLP-2]) that have distinct functions in regulating metabolism in mammals. In contrast, glucagon and GLP-1 have similar physiological actions in fish, that of mammalian glucagon. We have identified sequences similar to receptors for proglucagon-derived peptides from the genomes of two fish (pufferfish and zebrafish), a frog (Xenopus tropicalis), and a bird (chicken). Phylogenetic analysis of the receptor sequences suggested an explanation for the divergent function of GLP-1 in fish and mammals. The phylogeny of our predicted and characterized receptors for proglucagon-derived peptides demonstrate that receptors for glucagon, GLP-1, and GLP-2 have an origin before the divergence of fish and mammals; however, fish have lost the gene encoding the GLP-1 class of receptors, and likely the incretin action of GLP-1. Receptors that bind GLP-1, but yield glucagon-like action, have been characterized in goldfish and zebrafish, and these sequences are most closely related to glucagon receptors. Both pufferfish and zebrafish have a second glucagon receptor-like gene that is most closely related to the characterized goldfish glucagon receptor. The phylogeny of glucagon receptor-like genes in fish indicates that a duplication of the glucagon receptor gene occurred on the ancestral fish lineage, and could explain the shared action of glucagon and GLP-1. We suggest that the binding specificity of one of the duplicated glucagon receptors has diverged, yielding receptors for GLP-1 and glucagon, but that ancestral downstream signaling has been maintained, resulting in both receptors retaining glucagon-stimulated downstream effects.

glucagon is essential for alpha cell transdifferentiation and beta cell neogenesis

“…Indeed, glucagon and GLP-1 have similar effects on cAMP generation and hepatic glucose production in teleost fish (Chow et al, 2004). This might be due to loss of the ancestral GLP-1 receptor, together with the evolved capacity of a duplicated glucagon receptor to bind GLP-1 (Irwin and Wong, 2005). Thus, we speculate that in fish the glucagon signaling pathway executes some of the functions of GLP-1 in mammals.…”

Evolution of Hormone Function: Proglucagon-derived Peptides and Their Receptors

“…These searches resulted in the identification of several sequences from the chicken EST database that were most closely related to receptors for glucagon, GLP-1, GLP-2, or GIP. Overlapping ESTs were aligned and assembled into longer cDNA sequences (Irwin and Wong 2005).…”

“…The locations of exons and intervening introns of the receptor genes were identified by searching the genomic sequences for regions that were similar to amino acid sequences of known receptors. The boundaries of coding sequences (i.e., intron-exon boundaries) were established on the basis of rules developed for the identification of splice junction (Mount 1982) and the conservation of position and intron phase with respect to the well-characterized mammalian genes (Irwin and Gong 2003, Zhou and Irwin 2004, Irwin and Wong 2005. For the chicken genes, we took advantage of the partial cDNA sequences that were derived from ESTs to help predict exons and coding regions.…”

MOLECULAR EVOLUTION OF GPCRS: GLP1/GLP1 receptors

“…With regard to the concept of coevolution of the peptide and the receptor, the possibility remains that existing receptors recognize paralogous peptides in place of the missing orthologous partners. For example, fish GLP1 binds fish GCGRs with high affinity (Irwin & Wong 2005). Thus, it is possible that GLP1 has gained a GCG-like function in teleost fish (Nguyen et al 1994).…”