Amunine

CRF is synthesized and released by neuroendocrine cells in the paraventricular nucleus of the hypothalamus. Its precursor protein undergoes a series of processing modifications, ultimately forming a biologically active peptide of 41 amino acids. The synthesis and secretion of CRF are finely regulated by multiple factors.

In the basal state, the secretion of CRF maintains a certain rhythm to adapt to the normal physiological needs of the body. When the body encounters external stimuli such as trauma, infection, anxiety, fear, etc., these stimulus signals will be transmitted to the hypothalamus through the nervous system. Specifically, external stimuli can activate sensory organs and generate signals that are transmitted to the central nervous system, affecting the activity of CRF secreting cells through reflexive regulation.

Endogenous opioid peptides also have similar inhibitory effects, and CRF itself can inhibit its release by enhancing the activity of opioid peptides. The melatonin secreted by the pineal gland serves as a signal transmitted to the body by changes in the external environment, which can stimulate the body to adjust reproductive activity patterns. It exhibits a circadian rhythm in hormone secretion controlled by the hypothalamic pituitary axis. The effect of melatonin on the hypothalamic pituitary ovarian axis is inhibitory. It can prevent premature sexual maturation in childhood and prevent the hypothalamus from responding positively to estrogen in adulthood, thereby inhibiting the release of CRF and affecting ovulation.

The binding process between CRF and receptors exhibits a two-step activation mechanism. The structural analysis of cryo electron microscopy showed that CRF binds to the extracellular domain of CRF1R receptor through the C-terminus, which is the process of rapid recognition of ligand C-terminus by the receptor extracellular domain. Subsequently, the N-terminal alpha helix of CRF is inserted into the transmembrane region of the receptor, which is a crucial step in determining ligand specificity. This two-step recognition pattern prevents the occurrence of B-class GPCRs incorrectly recognizing ligands, ensuring the accuracy and specificity of signal transduction.

PKA phosphorylates multiple target proteins, promoting the synthesis and release of adrenocorticotropic hormone (ACTH).

ACTH travels with the blood to the adrenal cortex and acts on the zona fasciculata and zona reticulata of the adrenal cortex, promoting the secretion of glucocorticoids such as cortisol. Corticosteroids play a wide and important role in the body's response to stress. It can improve the body's tolerance to stress, regulate protein, fat, and carbohydrate metabolism, inhibit immune inflammatory reactions, and ensure the normal physiological functions of the body under stress. For example, under acute stress, the secretion of glucocorticoids increases, which can cause an increase in heart rate, blood pressure, muscle tension, metabolic levels, etc., putting the body into a state of readiness to respond to emergency situations.

Participate in stress response: In addition to regulating glucocorticoid secretion through the HPA axis to cope with stress, amunine also directly participates in other aspects of stress response. During acute stress, CRF secreted by hypothalamic paraventricular nucleus neurons can stimulate pituitary secretion of ACTH, while arginine vasopressin (AVP) is expressed in hypothalamic paraventricular nucleus CRH neurons and co released with CRH, enhancing the secretion of ACTH and cortisol. Cortisol exerts extensive and complex effects on the metabolic system, cardiovascular system, and immune response by binding to receptors, helping the body respond to emergency situations.

Impact on reproductive function: CRF is also expressed in the reproductive system and participates in the regulation of reproductive function. Research has found that CRF and its receptors are also expressed in peripheral tissues such as the placenta and gonads, and play a role in physiological activities such as childbirth initiation. In female animals, CRF may regulate the secretion of reproductive hormones by affecting the interaction between the HPA axis and the hypothalamic pituitary gonadal axis, thereby affecting the reproductive cycle and fertility. For example, in livestock such as sheep, the secretion changes of CRF may be related to the regulation of the breeding season.

In recent years, with the development of structural biology techniques, significant progress has been made in the molecular level study of the mechanism of action of CRF. With the cooperation of Xu Huaqiang Research Group of the Chinese Academy of Sciences Shanghai Institute of Materia Medica and Zhang Yan Research Group of the School of Basic Medicine of Zhejiang University, the three-dimensional structure of the complexes of CRF1R and CRF2R subtypes with Gs protein trimer under the activation of the endogenous ligand UCN1 was analyzed by means of freeze electron microscopy. The resolution rates were 3.0 Å and 2.8 Å, respectively.

Among them, TM6 unwind at a specific position and form a twist, which is stabilized by hydrogen bonds between specific amino acids, providing sufficient space for recruiting Gs proteins. The interaction between the transmembrane helix of the receptor and the α 5 helix of G α s, as well as the interaction between the Helix 8 helix of the receptor and the N-terminus of G β 1, are the main interfaces of interaction between the receptor and Gs protein. This highly conserved "NPGQ" amino acid in B-class GPCRs and its interaction interface with Gs further reveal the universal mechanism of B-class GPCR activation.