CRH ligands bind to two highly homologous receptors,
CRHR1 and CRHR2, which belong to the G-protein-coupled
receptor family (Fig. 1).21 CRHR1 and CRHR2 bind differentially
to each of the CRH family members. CRHR1 shows
high affinity for CRH and Ucn I, but no appreciable affinity
for Ucn II and Ucn III. CRHR2 binds with greater affinity to
Ucn I, Ucn II, and Ucn III than to CRH. Extensive alternate
splicing of CRHR1 and CRHR2 produces various isoforms:
CRHR1α, CRHR2α, CRHR2β, and CRHR2γ.22 In general,
CRHR1 mediates the “fight-or-flight” stress response through
the CRH-ACTH-glucocorticoid axis, whereas CRHR2 mediates
stress-coping responses through Ucn II (stresscopin)
and Ucn III (stresscopin-related peptide).23
CRHR1-deficient mice exhibited a marked decrease in the
size of the zona fasciculata region of the adrenal gland and
thus had a low plasma concentration of corticosterone.24
Although basal ACTH secretion was normal in these mice,
restraint stress did not increase circulating ACTH levels. The
progeny born to homozygous mutant females developed
lung dysplasia with alveolar collapse and emphysema and
died within 2 days after birth. In utero corticosterone treatment
rescued the phenotype. The mutant mice were less
sensitive to anxiogenic-like stimuli, suggesting that CRHR1 is
required for a normal anxiety response.
CRH ligands bind to two highly homologous receptors,
CRHR1 and CRHR2, which belong to the G-protein-coupled
receptor family (Fig. 1).21 CRHR1 and CRHR2 bind differentially
to each of the CRH family members. CRHR1 shows
high affinity for CRH and Ucn I, but no appreciable affinity
for Ucn II and Ucn III. CRHR2 binds with greater affinity to
Ucn I, Ucn II, and Ucn III than to CRH. Extensive alternate
splicing of CRHR1 and CRHR2 produces various isoforms:
CRHR1α, CRHR2α, CRHR2β, and CRHR2γ.22 In general,
CRHR1 mediates the “fight-or-flight” stress response through
the CRH-ACTH-glucocorticoid axis, whereas CRHR2 mediates
stress-coping responses through Ucn II (stresscopin)
and Ucn III (stresscopin-related peptide).23
CRHR1-deficient mice exhibited a marked decrease in the
size of the zona fasciculata region of the adrenal gland and
thus had a low plasma concentration of corticosterone.24
Although basal ACTH secretion was normal in these mice,
restraint stress did not increase circulating ACTH levels. The
progeny born to homozygous mutant females developed
lung dysplasia with alveolar collapse and emphysema and
died within 2 days after birth. In utero corticosterone treatment
rescued the phenotype. The mutant mice were less
sensitive to anxiogenic-like stimuli, suggesting that CRHR1 is
required for a normal anxiety response.
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