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Hormones are the first messengers that trigger the various biological and physiological processes inside the body. Among the various types of hormones, steroid hormones are important because of their hydrophobic in nature. The main precursor of the steroid hormones is cholesterol that is why they are hydrophobic in nature and can pass through the cell membrane. Steroid hormones can also regulate gene expression involving the nuclear receptors.
20-hydroxyecdysone or 20E is a steroid hormone that is found in both insects and plants. In insect, dietary cholesterol is first converted to ecdysone in the prothoratic gland. Ecdysone is then converted to 20E, a hydrophobic steroid hormone that can easily pass through the cell membrane and nuclear membrane. Inside the nucleus, it interacts with the nuclear ecdysone receptor (EcR) to initiate the expression of the target genes.
Interaction of 20E with EcR promotes binding of EcR to the ultraspiracle (USP) to form a heterodimer (EcR/USP, a transcription complex). Thus formed transcription complex binds to the ecdysone response element (EcRE) to promote expression of the hormone receptor 3 (HR3). HR3 is a delayed-early gene that is involved in insect development and morphogenesis. This is the genomic pathway that I just mentioned.
However, 20E is also involved in the non-genomic pathway in certain insects where it involves the activation of the G-protein-coupled cell surface receptors, calcium signaling and protein kinase C (PKC). Involvement of PKA signaling cascade is necessary for the phosphorylation of the USP, the genomic pathway of the 20E-induced signaling pathway. Therefore, 20E-induces signaling pathway follows both, genomic and non-genomic signaling cascade to trigger gene expression.
In a study conducted in Drosophila melanogaster, it has been shown that 20E can bind to the dopamine/ecdysteroid receptor and promotes the formation of the cAMP formation, an intracellular second messenger that is formed from AMP. The membrane-bound adenylyl cyclase catalyzes the conversion of AMP to cAMP. cAMP, once formed, binds to the regulatory subunits of the PKA promoting dissociation of the PKA into two regulatory and two catalytic subunits; PAKR (regulatory subunit) and PKAC (catalytic subunit).
Thus activated catalytic subunit of the PKA (PKAC) is translocated into the nucleus where it phosphorylates the cAMP response element-binding protein (CREB). Phosphorylated CREB forms a homodimer and binds to the cAMP response element (CRE) located in the 5’ region of the target gene and promote/repress gene expression.
The cAMP-regulated PKA/CREB signaling pathway is a major signaling pathway mediated by many hormones. For example, estrogen promotes cAMP production via G-protein-coupled cell surface receptors while it represses the mitogen-activated protein kinase (MAPK) signaling cascade via cAMP/PKA pathway.
HR3 (a 20E-responsive transcription factor) acts as a developmental switch during the development and metamorphosis of the insect. For example, D. melanogaster HR3 (DHR3) is rapidly expressed in response to the 20E during the late third instar larvae and early prepupae. During that time, DHR3 is required for the maximal expression of the genes such as EcR, E74B; midprepupal regulatory genes. These genes help prepupal-pupal transition during the metamorphosis if the D. melanogaster.