Types of Receptors: Internal Receptors

Internal receptors are soluble proteins located in the cytoplasm or nucleus that bind hydrophobic signaling molecules inside cells. Unlike types of receptors cell surface receptors, which bind hydrophilic ligands outside the cell, internal receptors allow small, non-polar molecules to diffuse through the plasma membrane and trigger intracellular responses such as changes in gene expression.

Internal receptors bind hydrophobic, non-polar signaling molecules that can cross the plasma membrane. Examples include steroid hormones like testosterone and estrogen, their enzymatically processed forms such as dihydrotestosterone (DHT), and nitric oxide gas. These molecules either diffuse through the membrane or are synthesized within the cell.

When testosterone or DHT binds to the androgen receptor in the cytoplasm, the receptor-ligand complex undergoes a conformational change and moves into the nucleus where it dimerizes. The activated receptor recognizes and binds to specific DNA sequences called androgen-response elements, modulating gene activity to promote or block synthesis of mRNAs that mediate androgen-specific cellular effects.

Internal receptors located in the cytoplasm must cross the nuclear membrane because their target DNA-binding sites are located within the nucleus. After ligand binding and dimerization, the activated receptor-ligand complex translocates into the nucleus to access hormone or androgen-response elements and regulate transcription of target genes.

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

Once activated by ligand binding, internal receptors function like transcription factors by binding to specific DNA sequences called response elements. This binding modulates the activity of target genes, either promoting or blocking mRNA synthesis. The outcome depends on the receptor type, DNA sequence, and presence of other transcription factors and co-activators.

Thyroid hormone receptors usually reside in the nucleus, unlike cytoplasmic internal receptors. Because these receptors are already nuclear, their ligands must cross both the plasma membrane and nuclear membrane to reach and activate them. This nuclear localization distinguishes thyroid hormone signaling from steroid hormone pathways that begin in the cytoplasm.