Mineralocorticoid receptors: evolutionary and pathophysiological considerations.

Area of Science:

• Molecular biology
• Evolutionary biology
• Genetics

Background:

• Nuclear receptors, including MR, GR, PR, and AR, are crucial for homeostasis and development.
• The evolutionary history and diversification of this nuclear receptor subfamily remain poorly understood.
• Conflicting models exist regarding the evolutionary pathways of these related receptors.

Purpose of the Study:

• To elucidate the evolutionary relationships within the MR, GR, PR, and AR subfamily.
• To resolve conflicting models of nuclear receptor subfamily evolution.
• To determine the ancestral state and divergence order of these critical receptors.

Main Methods:

• Phylogenetic analyses using Bayesian and maximum likelihood approaches.
• Topological constraint analyses to compare seven distinct evolutionary models.
• Ancestral state reconstructions at functionally significant receptor sites.

Main Results:

• Phylogenetic trees consistently place MR in a basal position, with PR and AR forming a sister clade.
• Three evolutionary models showed similar support, with variations in the earliest diverging member (MR or GR).
• Ancestral state reconstruction suggests MR's S810L mutation reflects an ancestral sequence, supporting MR's early divergence.

Conclusions:

• The mineralocorticoid receptor (MR) was likely the first to diverge from the ancestral gene lineage of this subfamily.
• Phylogenetic and pathophysiological evidence supports a specific evolutionary trajectory for these nuclear receptors.
• Understanding receptor evolution provides insights into their roles in homeostasis and development.