Receptor Highlight Series: Nuclear Receptors 🧬
Unlike the transmembrane receptors, nuclear receptors are found inside the cell, either within the nucleus or in the cytoplasm. These receptors bind with, most commonly, lipid-soluble ligands like steroid hormones, thyroid hormones, or fat-soluble vitamins, among others.
Hello again, and welcome back to the Receptor Highlight Series! In this installment, we’re moving away from our typical discussion at the cell membrane and diving deeper – literally. Today, we will focus on nuclear receptors, a unique class of receptors that work inside the cell.
Unlike the transmembrane receptors, nuclear receptors are found inside the cell, either within the nucleus or in the cytoplasm. These receptors bind with, most commonly, lipid-soluble ligands like steroid hormones, thyroid hormones, or fat-soluble vitamins, among others. Due to the lipid-soluble nature of these ligands, they can easily diffuse across the cell's phospholipid bilayer, quite different from the secondary signaling cascades we've talked about in the past. It's like bypassing the front desk and walking straight into the boss’s office.
Nuclear receptors generally have three main domains:
- A ligand-binding domain that binds the hormone/signaling molecule
- A DNA-binding domain that interacts with specific gene sequences and includes one of my favorite structural components, zinc fingers! I mean, it's just fun to say to be honest..
- A transactivation domain that influences transcription, either activating or repressing target gene transcription
When a ligand (like cortisol or triiodothyronine[T3]) binds to the receptor, and when all necessary cofactors are present, it causes a conformational change that allows the receptor to either:
- Pair with another hormone-bound receptor (homodimerization or heterodimerization) before being shuttled to the DNA or,
- Bind directly to DNA at hormone response elements (HREs)
This ultimately allows for altered gene transcription, upregulating (histone acetylation) or downregulating (histone deacetylation) genes of specific proteins.
Some nuclear receptors (like the glucocorticoid receptor) are found in the cytoplasm, held in an inactive state by chaperone proteins (heat shock proteins in the case of glucocorticoid receptors). Once the ligand binds, these receptors undergo conformational changes and translocate into the nucleus. Others, like thyroid hormone receptors, reside in the nucleus at all times, waiting for their ligand to arrive before enacting their effects, gene regulation!
Here's a more holistic view of the bigger picture. Your adrenal glands release cortisol in response to stress or just typical cyclic production, which travels throughout your bloodstream to different areas of your body where it may slip through the cell membrane and bind to its receptor in the cytoplasm. Together, they move into the nucleus and influence the transcription of anti-inflammatory proteins while suppressing pro-inflammatory ones.
This mechanism is why steroids (like prednisone) are powerful anti-inflammatory medications by mimicking cortisol’s ability to dial down immune responses through nuclear receptor signaling.
A few other examples of nuclear receptors include:
- Estrogen/Testosterone Receptors → crucial in sexual development
- Thyroid Hormone Receptors → regulate metabolic rate
- Vitamin D Receptor → regulates calcium homeostasis
Each one has a unique set of ligands and gene targets, but they all operate through a common mechanism: modulating gene expression!
Thanks again for joining me on another stop in the Receptor Highlight Series! Whether they’re regulating metabolism, development, or cellular differentiation, nuclear receptors show us the power of precise control. See you next time!
References:
https://pubmed.ncbi.nlm.nih.gov/29367089/
https://pmc.ncbi.nlm.nih.gov/articles/PMC4087167/
https://www.sciencedirect.com/science/article/pii/S0021925820363894
*Information presented on RxTeach does not represent the opinion of any specific company, organization, or team other than the authors themselves. No patient-provider relationship is created.