A smoothened agonist activates the Smoothened (Smo) protein. This activation influences various biological processes, including cell growth, differentiation, and tissue maintenance. Scientists are exploring smoothened agonists for their potential to address medical conditions where Smoothened protein activity is insufficient, holding promise for new therapeutic approaches.
The Smoothened Protein and Its Role
The Smoothened protein is a cell surface receptor central to the Hedgehog (Hh) signaling pathway. This pathway guides embryonic development and maintains healthy adult tissues. Smoothened, a G protein-coupled receptor (GPCR), transmits signals across the cell membrane.
Normally, Patched (Ptc) inhibits Smoothened. When a Hedgehog signaling molecule binds to Patched, Patched releases its inhibition on Smoothened. This activates Smoothened, triggering a cascade of intracellular events. This pathway, regulated by Smoothened, is important for processes like stem cell proliferation and organ development.
How Agonists Activate Smoothened
An agonist is a molecule that binds to a receptor and initiates a biological response. For the Smoothened protein, an agonist directly interacts with the Smoothened receptor, leading to its activation. This binding causes a change in Smoothened’s shape, allowing it to send signals into the cell.
When a smoothened agonist binds, it mimics the natural activation process, effectively “turning on” the protein. This activation enables Smoothened to translocate within the cell, often to the primary cilium in vertebrates, a small, hair-like projection on the cell surface.
Once activated, Smoothened initiates downstream cellular responses, including the activation of transcription factors like the Gli family. These Gli transcription factors then move into the cell’s nucleus and influence the expression of specific genes, ultimately altering cell behavior and fate. Agonists like SAG achieve this by binding to the heptahelical bundle of Smoothened, stabilizing a conformation that leads to increased downstream gene expression.
Developing Treatments with Smoothened Agonists
Activating Smoothened with agonists benefits medical conditions where the Hedgehog signaling pathway is underactive. Research explores their use in regenerative medicine to stimulate natural repair. They could reactivate or enhance tissue repair in conditions like heart failure, neuronal injury, wound healing, and retinal damage.
For example, purmorphamine shows neuroprotective properties and promotes regeneration after ischemic brain injury. SAG improves neuronal differentiation of human induced pluripotent stem cells and induces proliferation and survival of neuronal and glial precursors. SAG also prevents glucocorticoid-induced brain injury and rescues cerebellar development in a mouse model of Down syndrome. These agonists are also being investigated for promoting myelin regeneration in demyelinating diseases.