Internal Receptors

Internal receptors bind hydrophobic, non-polar signaling molecules that can diffuse through the plasma membrane, such as steroid hormones like testosterone and estrogen. Some ligands are synthesized intracellularly, like nitric oxide gas. These molecules differ from hydrophilic signals that cannot cross the membrane and require membrane-bound receptors instead.

When testosterone or its converted form DHT binds to an androgen receptor in the cytoplasm, the ligand-receptor complex undergoes conformational changes, moves to the nucleus, and dimerizes. The activated complex then binds to DNA-binding sites called androgen-response elements, which modulate gene activity by promoting or blocking mRNA synthesis to produce androgen-specific cellular effects.

Cytoplasmic internal receptors must cross the nuclear membrane because their target DNA-binding sites, called response elements, are located in the nucleus. Once the ligand-receptor complex forms in the cytoplasm, it translocates across the nuclear membrane to access these specific DNA sequences and regulate transcription of target genes.

Estrogen diffuses across the plasma membrane and binds to its cytoplasmic receptor, triggering dimerization of receptor molecules. The ligand-receptor complex then transports to the nucleus and binds to Estrogen-Response Elements (EREs) on DNA. Depending on co-activators and other transcription factors present, this binding increases or decreases transcription of target genes.

Unlike steroid hormone receptors that reside in the cytoplasm, some thyroid hormone receptors are located directly in the nucleus. These nuclear-resident receptors require ligands to cross both the plasma membrane and nuclear membrane to reach them. Once activated, they bind to DNA and regulate transcription similarly to cytoplasmic internal receptors.

Ligand binding induces a conformational change in the internal receptor that enables it to bind other cellular molecules. This structural rearrangement allows the receptor to expose its DNA-binding domain, facilitating dimerization and nuclear translocation. The activated receptor can then recognize and bind specific DNA sequences to regulate gene expression.

Response elements are specific DNA sequences recognized by activated internal receptor complexes. When receptors bind to these sites, they either promote or block mRNA synthesis of target genes depending on the presence of co-activators and other transcription factors. This mechanism allows cells to produce hormone-specific responses through selective gene regulation.