Steroid hormone-mediated cAMP/PKA/CREB signaling pathway

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Steroid hormone mediated CREB signaling pathway — A schematic representation of the 20E-induced cAMP/PKA/CREB signaling pathway involved in the gene regulation. **Credit: Jing et al., 2016**

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 nature. The main precursor of the steroid hormones is cholesterol which is why they are hydrophobic in nature and can pass through the cell membrane. Steroid hormones can also regulate gene expression involving nuclear receptors.

20-hydroxyecdysone or 20E is a steroid hormone that is found in both insects and plants. In insects, 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 the 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 the 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). The involvement of the PKA signaling cascade is necessary for the phosphorylation of the USP, the genomic pathway of the 20E-induced signaling pathway. Therefore, the 20E-induces signaling pathway follows both, genomic and non-genomic signaling cascades 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 promotes/represses 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 the 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 of the D. melanogaster.

To study the role and mechanism of the cAMP-induced protein kinase A-CREB (PKA/CREB) signaling pathway mediated by 20E and its relation with the Ca++-induced protein kinase C, researchers took Helicoverpa. armigera (an agricultural pest) in which they studied the roles of the PKA and CREB in the 20E-induced expression of the target genes.

During the study, they found that the 20E steroid hormone triggers the PKAC1 phosphorylation via ErGPCR2. Thus phosphorylated PKAC1 is then translocated into the nucleus where it phosphorylates the CREB. Phosphorylated CREB protein binds to the CRE sequence located in the 5’ region of the HHR3 gene leading to the 20E-induced gene expression.

In conclusion, 20E mediates its effect through the GPCR-cAMP-PKA pathway thereby enhancing the 20E-induced gene transcription via GPCR-Ca+2-PKC-activated EcR/USP pathway. In another way, the 20E steroid hormone exerts its effect via the ErGPCR-cAMP-PKA-CREB (non-genomic) pathway prior to the initiation of the gene expression through the EcR/UPS (genomic) pathway.