MOLECULAR EVOLUTION OF GPCRS: CRH/CRH receptors

Abstract

Corticotrophin-releasing hormone (CRH) is the pivotal neuroendocrine peptide hormone associated with the regulation of the stress response in vertebrates. However, CRH-like peptides are also found in a number of invertebrate species. The origin of this peptide can be traced to a common ancestor of lineages leading to chordates and to arthropods, postulated to occur some 500 million years ago. Evidence indicates the presence of a single CRH-like receptor and a soluble binding protein system that acted to transduce and regulate the actions of the early CRH peptide. In vertebrates, genome duplications led to the divergence of CRH receptors into CRH1 and CRH2 forms in tandem with the development of four paralogous ligand lineages that included CRH; urotensin I/urocortin (Ucn), Ucn2 and Ucn3. In addition, taxon-specific genome duplications led to further local divergences in CRH ligands and receptors. Functionally, the CRH ligand-receptor system evolved initially as a molecular system to integrate early diuresis and nutrient acquisition. As multicellular organisms evolved into more complex forms, this ligand-receptor system became integrated with the organismal stress response to coordinate homoeostatic challenges with internal energy usage. In vertebrates, CRH and the CRH1 receptor became associated with the hypothalamo-pituitary-adrenal/interrenal axis and the initial stress response, whereas the CRH2 receptor was selected to play a greater role in diuresis, nutrient acquisition and the latter aspects of the stress response.

Corticotropin-releasing hormone family evolution: five ancestral genes remain in some lineages

“…The CRH/DH-like peptides bind and activate a group of receptors that belong to class B of the G-proteincoupled receptors (GPCRs) (Hwang et al 2013, Cardoso et al 2014, Lovejoy et al 2014. Vertebrates usually have two highly conserved CRH receptors (CRHR1 and CRHR2) that arose by gene duplication in the two rounds of basal vertebrate genome doubling (Cardoso et al 2014), the so-called 1R and 2R events (Nakatani et al 2007, Putnam et al 2008.…”

“…The model by Lovejoy and coworkers proposed that a single ancestral gene was duplicated in the first tetraploidization event, resulting in the CRH/UCN1 ancestor and UCN2/UCN3 ancestor. Subsequently, the second tetraploidization generated the extant quartet (Lovejoy & de Lannoy 2013, Lovejoy et al 2014). The other model put forth by Hwang and coworkers is based on the chromosomal locations of the four peptide genes in two separate paralogons (Hwang et al 2013).…”

Evolutionary origin of the type 2 corticotropin‐releasing hormone receptor γ splice variant

“…Most vertebrates have two types of CRH receptors, CRHR1 and CRHR2, encoded by two different genes. This is thought to be the result of a genome duplication during early chordate evolution, in which an ancestral crhr gene, present before the bifurcation of deuterostomes and protostomes, gave rise to two CRHRs that subsequently diverged into CRHR1 and CRHR2 in chordates (Lovejoy, Chang, Lovejoy, & Castillo, ). Despite their highly conserved sequence, the two CRHR types have distinct pharmacological properties and expression patterns, and hence different roles (Hauger et al, ; Hillhouse & Grammatopoulos, ).…”

The Nutrient and Energy Sensor Sirt1 Regulates the Hypothalamic-Pituitary-Adrenal (HPA) Axis by Altering the Production of the Prohormone Convertase 2 (PC2) Essential in the Maturation of Corticotropin-releasing Hormone (CRH) from Its Prohormone in Male Rats

“…Upon binding to its cognate receptor, corticotropin-releasing hormone receptor 1 (CRHR1) (25), which is expressed by corticotropic cells of the adenohypophysis, CRH stimulates the synthesis and secretion of adrenocorticotropic hormone (ACTH) as well as other bioactive molecules such as ␤-endorphin (26). ACTH engages the melanocortin 2 receptor expressed by cells of the adrenal cortex and stimulates the production and secretion of steroid hormones such as GC (27).…”