Corticotropin-releasing hormone-binding protein and stress: from invertebrates to humans

Abstract

Corticotropin-releasing hormone (CRH) is a key regulator of the stress response. This peptide controls the hypothalamic-pituitary-adrenal (HPA) axis as well as a variety of behavioral and autonomic stress responses via the two CRH receptors, CRH-R1 and CRH-R2. The CRH system also includes an evolutionarily conserved CRH-binding protein (CRH-BP), a secreted glycoprotein that binds CRH with subnanomolar affinity to modulate CRH receptor activity. In this review, we discuss the current literature on CRH-BP and stress across multiple species, from insects to humans. We describe the regulation of CRH-BP in response to stress, as well as genetic mouse models that have been utilized to elucidate the in vivo role(s) of CRH-BP in modulating the stress response. Finally, the role of CRH-BP in the human stress response is examined, including single nucleotide polymorphisms in the human CRHBP gene that are associated with stress-related affective disorders and addiction. Lay summary The stress response is controlled by corticotropin-releasing hormone (CRH), acting via CRH receptors. However, the CRH system also includes a unique CRH-binding protein (CRH-BP) that binds CRH with an affinity greater than the CRH receptors. In this review, we discuss the role of this highly conserved CRH-BP in regulation of the CRH-mediated stress response from invertebrates to humans.

Keywords: CRH receptors; CRH-binding protein; Corticotropin-releasing hormone; corticotropin-releasing factor; glucocorticoids; stress.

Figure 1.

Alignment of amino acid sequences of members of the CRH/UCN1 and UCN2/UCN3 families. Conserved amino acid residues are color-coded as follows: yellow for CRH (between species); blue for UCN1/urotensin/sauvagine; green for residues common between CRH and UCN1/urotensin/sauvagine peptides; pink for UCN2/UCN3. Amino acids common between all peptides listed are marked with an asterisk (*). Abbreviations listed: M, mouse; R, rat; H, human; O, ovine. The accession numbers are as follows: Human CRH, NP_000747.1; Mouse CRH, NP_991338.1; Rat CRH, P01143; Ovine CRH, P01142; Xenopus CRH, P49188; Carp CRH, CAC84859; Carp Urotensin 1, P01146; Painted-Belly Leaf Frog Sauvagine, P01144; Mouse UCN1, P81615; Rat UCN1, P55090; Ovine UCN1, AAC27288; Human UCN1, NP_003344; Mouse UCN2, Q99ML8.2; Human UCN2, NP_149976; Mouse UCN3, Q924A4.1; Human UCN3, NP_444277.

Figure 2.

Potential roles for CRH-BP. A. CRH-BP may bind CRH and inhibit CRH receptor activation and downstream signaling. B. CRH-BP may bind CRH and enhance activation of CRH-R2 and downstream signaling. C. CRH-BP may have CRH receptor-independent signaling roles. D. CRH-BP may act as an escort protein to traffic CRH-R2± to the plasma membrane. This figure is modified from Westphal and Seasholtz, 2006.