Stepwise loss of motilin and its specific receptor genes in rodents

Abstract

Specific interactions among biomolecules drive virtually all cellular functions and underlie phenotypic complexity and diversity. Biomolecules are not isolated particles, but are elements of integrated interaction networks, and play their roles through specific interactions. Simultaneous emergence or loss of multiple interacting partners is unlikely. If one of the interacting partners is lost, then what are the evolutionary consequences for the retained partner? Taking advantages of the availability of the large number of mammalian genome sequences and knowledge of phylogenetic relationships of the species, we examined the evolutionary fate of the motilin (MLN) hormone gene, after the pseudogenization of its specific receptor, MLN receptor (MLNR), on the rodent lineage. We speculate that the MLNR gene became a pseudogene before the divergence of the squirrel and other rodents about 75 mya. The evolutionary consequences for the MLN gene were diverse. While an intact open reading frame for the MLN gene, which appears functional, was preserved in the kangaroo rat, the MLN gene became inactivated independently on the lineages leading to the guinea pig and the common ancestor of the mouse and rat. Gain and loss of specific interactions among biomolecules through the birth and death of genes for biomolecules point to a general evolutionary dynamic: gene birth and death are widespread phenomena in genome evolution, at the genetic level; thus, once mutations arise, a stepwise process of elaboration and optimization ensues, which gradually integrates and orders mutations into a coherent pattern.

In vitro selection of a peptide antagonist of growth hormone secretagogue receptor using cDNA display

“…Suncus stomachs were used for in vitro contraction experiments. Motilin is a peptide hormone that stimulates gastric contraction similarly to ghrelin, and it is not expressed in rodents such as mice and rats (52). Suncus murinus is a small mammal that expresses both motilin and ghrelin; thus, it can be used to study motilin-ghrelin family peptides (53).…”

Motilin stimulates preadipocyte proliferation and differentiation and adipocyte lipid storage

“…In mice, although it is still debated whether or not native GPR38 (motilin receptor) is expressed (15), central administrations of motilin and GM-109 (a motilin antagonist) were respectively shown to increase food intake and reduce anxiety (1,27). These and numerous other studies suggest that rodents are a useful model for motilin studies.…”

“…In human and animal (mainly rabbit and pig) models, GPR38 is expressed in the smooth muscle layer and the mucosa of the GI tract, the amygdala, the mesenteric neurons, and the hippocampus (21,40,41,49). In mice, it is presently debated whether or not the motilin receptor is truly expressed or is simply present as a pseudogene (15). Meanwhile, direct motilin injection or administration of GPR38 agonists and antagonists were shown to induce biological effects in rodents (2,36).…”

The motilin receptor agonist erythromycin stimulates hunger and food intake through a cholinergic pathway

“…Studies in rodents have shown that motilin administration can stimulate food intake (27,28). However, these results need to be interpreted with caution because other studies reported that motilin and the motilin receptor exist only as pseudogenes in rodents and are therefore not functional (29,30) Although the expression of motilin and the motilin receptor has been demonstrated in humans, studies on the effect of motilin on food intake in humans are lacking (13,31,32). In this study, we have shown that the effect of the motilin receptor agonist erythromycin on hunger is regulated via a cholinergic pathway because pretreatment with atropine abolished both the increase in hunger and the induction of phase III contractions.…”