Chemical Identity

Property	Value
Name	Corticotropin-Releasing Hormone (CRH)
Gene	CRH (chromosome 8q13)
Sequence	Ser-Glu-Glu-Pro-Pro-Ser-Ser-Leu-Glu-Leu-Arg-Glu-Val-Leu-Glu-Met-Thr-Arg-Ala-Val-Leu-Gln-Asp-Ala-His-Leu-Gln-Ala-Val-Leu-Ser-Gln-Lys-Leu-Glu-Lys-Lys-Tyr-Gln-Asn-Lys-Pro-Pro-Glu-Asp
Length	41 amino acids
Chemical Formula	C₂₀₈H₃₃₆N₅₆O₆₀S
Molecular Weight	4758.0 Da
PDB Structures	1GO1 (NMR), 1MT9 (NMR)

Structure

CRH is an unstructured peptide in solution but adopts a helical conformation when bound to its receptor:

• N-terminal residues 1-8: Receptor binding
• Residues 8-30: α-helical segment (in membrane environment)
• C-terminal residues 30-41: Amphipathic, membrane-associated

Receptors

Receptor	Gene	Distribution	Effects
CRH-R1	CRHR1	Anterior pituitary, cortex, cerebellum	ACTH release, anxiety
CRH-R2	CRHR2	Heart, vasculature, hypothalamus	Cardiovascular, anxiolytic

The HPA Axis

Stress → Hypothalamus → CRH release
    → Anterior pituitary → CRH-R1 → ACTH release
    → Adrenal cortex → Cortisol release
    → Negative feedback (cortisol → hypothalamus)

CRH-Binding Protein (CRH-BP)

• Circulates in blood, binds CRH with high affinity
• Modulates CRH bioavailability
• Elevated in pregnancy, stress

Physiological Functions

Stress Response

• CRH is the primary initiator of the HPA axis
• Stressful stimuli → parvocellular neurons → CRH release
• CRH → ACTH → Cortisol → metabolic/immune/behavioral effects

Feeding Behavior

• Central CRH suppresses appetite (anorexigenic)
• CRH-R1 in hypothalamus mediates feeding suppression
• CRH-R2 may mediate anxiety-related feeding changes

Anxiety and Depression

• Anxiety: CRH-R1 activation in amygdala, bed nucleus of stria terminalis
• Depression: Chronic stress → CRH hyperactivity → depressive behavior
• PTSD: Elevated CRH levels, altered HPA axis regulation

Clinical Significance

Dexamethasone Suppression Test (DST)

• Normal: Dexamethasone suppresses ACTH and cortisol
• Cushing’s disease: Cortisol escapes suppression
• Depression: Partial non-suppression (non-specific)

CRH Stimulation Test

• CRH IV → measure ACTH and cortisol
• Cushing’s disease: Exaggerated ACTH response
• Secondary adrenal insufficiency: Blunted response

Therapeutic Targets

Target	Drug/Strategy	Status
CRH-R1 antagonist	Pexacerfont	Phase III (discontinued)
CRH-R1 antagonist	Antalarmin	Research
CRH-BP	Recombinant CRH-BP	Research

Disease Associations

• Cushing’s disease: CRH-producing pituitary adenomas
• Depression: HPA axis hyperactivity
• Anxiety disorders: CRH-R1 overactivation
• Chronic fatigue syndrome: HPA axis dysfunction

Biosynthesis

1. Gene: CRH (chromosome 8q13)
2. PreproCRH (196 aa) → Signal peptide cleavage
3. ProCRH (173 aa) → Proteolytic processing
4. CRH (41 aa) + CRH-BP binding protein region
5. Storage: Large dense-core vesicles
6. Release: Stress-dependent exocytosis

Manufacturing

• SPPS (Fmoc): Standard solid-phase synthesis
• Purification: RP-HPLC, ion-exchange
• Characterization: Mass spectrometry, CD spectroscopy
• Ovine CRH: 41 aa, 70% homology to human (research standard)

References

1. Vale W, et al. “Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and β-endorphin.” FEBS Letters 168:1-6, 1981. doi:10.1016/0014-5793(81)80676-8
2. Chrousos GP. “The HPA axis and the stress response.” Endocrinology 149:3642-3648, 2008.
3. Rivier C, Vale W. “Modulation of stress-induced ACTH release by corticotropin-releasing factor.” Endocrinology 113:1421-1426, 1983.
4. Heinrichs SC, et al. “CRH knockout mice: a model for stress-related disorders.” Recent Progress in Hormone Research 57:377-390, 2002.
5. Holsboer F, Ising M. “Central CRH system in depression and anxiety.” Pharmacological Reviews 62:21-61, 2010.