Intracellular Receptors

Cell signaling and intracellular receptors

Cells respond to signals from their environment through a process known as cell signaling. A signal is transmitted when a signaling molecule called a ligand binds to a receptor protein in the target cell. This signal leads to a specific cellular response such as cell division and cell death.

The receptors involved in cell signaling can be broadly classified into two types: cell-surface receptors and intracellular receptors.

Cell-surface receptors span the plasma membrane with each receptor having extracellular, transmembrane, and cytoplasmic regions. When a ligand binds to a cell-surface receptor, extracellular signals are transformed into intracellular signals in a process called signal transduction.

On the other hand, intracellular receptors (also known as internal receptors) are found inside the cell.

They bind small hydrophobic or nonpolar ligands like steroid hormones, thyroid hormones, and vitamin D. Unlike cell-surface receptors, ligands that bind intracellular receptors can easily diffuse across the plasma membrane so they do not need to transmit the signal to other receptors or messengers via signal transduction. They can instead directly activate the intracellular receptor to effect cellular activation.

How do intracellular receptors function?

The stimulation of intracellular receptors typically results in modified transcription during gene expression.

Gene expression is the process by which information contained in a cell’s DNA is transformed into an amino acid sequence which ultimately becomes a protein. Transcription is a stage in gene expression in which the information contained in a cell’s DNA is copied into a type of RNA called messenger RNA (mRNA). The mRNA is used in protein synthesis.

While ligands are structurally diverse, intracellular receptors tend to share similar features because of their intrinsic transcription activity.

Intracellular receptors generally have three core domains: ligand-binding domain, a DNA-binding domain, and a transcription-activating domain.

• The ligand-binding (or carboxy-terminus) domain is the part of the receptor that is responsible for binding with hormones and other ligands.

• The DNA-binding domain consists of amino acids and is responsible for the receptor binding to segments of the DNA strand.

• The transcription-activating (or amino-terminus) domain is involved in initiating transcription by interacting with components that participate in transcription.

Besides these three core domains, there are two other domains that are typically found in receptor proteins:

• The nuclear localization sequence consists of short peptides. It facilitates the translocation of proteins from the cytoplasm to the nucleus.

• The dimerization domain is involved in bringing two receptors together as a dimer so that it can bind DNA.

What are the types of intracellular receptors and how do they work?

Intracellular receptors can be subdivided into two types: type I or cytoplasmic receptors and type II or nuclear receptors.

Type I intracellular receptors

Type I intracellular receptors (also known as cytoplasmic receptors) are anchored in the cytoplasm of a cell by chaperone proteins. These proteins also keep the receptors in an inactive state.

When a ligand binds with a type I intracellular receptor (forming the "ligand-receptor complex"), the chaperone proteins dissociate from the receptor, allowing the receptor to form a homodimer with other receptors and to undergo conformational change such that a nuclear localization sequence is exposed.

This transformation allows the receptor to enter the nucleus of the cell. Then, the ligand-receptor complex binds to specific regulatory sections in chromosomal DNA through its DNA-binding region and prompts the initiation of transcription.

Examples of type I intracellular receptors include androgen receptors and progesterone receptors. Testosterone and dihydrotestosterone (DHT) are ligands that bind androgen receptors in the cytoplasm and translocate them to the nucleus, initiating cellular processes like protein synthesis, cell growth, gonad formation, and development of secondary sex characteristics (Fig. 1).

Fig. 1 Testosterone and DHT bind androgen receptors in the cytoplasm. They are then translocated to the nucleus where they will alter transcription and cause biological changes such as the development of secondary sex characteristics.

On the other hand, the binding of ligand progesterone to progesterone receptors in the cytoplasm activates transcription that affects different biological processes including the menstrual cycle.

Type II intracellular receptors

Type II intracellular receptors (also known as nuclear receptors) are found in the nucleus of a cell. Because they are already in the nucleus, type II intracellular receptors can directly modify transcription without undergoing translocation. They typically form heterodimers with other nuclear receptors. Examples of type II intracellular receptors include retinoic acid receptors and thyroid receptors.

Thyroid hormone receptors play a role in regulating metabolism and cardiac function. When thyroid receptors are under-stimulated (for example, when a person suffers from hypothyroidism) their metabolism slows down which manifests in symptoms including fatigue, lethargy, weight gain, and reduced heart rate. When thyroid receptors are overstimulated (for example, when a person suffers from hyperthyroidism), their metabolism increases, leading to nervousness, weight loss, increased heart rate, among others.

What are other examples of intracellular receptors?

In this section, we’ll discuss examples of intracellular hormone receptors and nitric oxide receptors.

Intracellular hormone receptors

Hormones are signaling molecules that are created in one region of the body and have the ability to cause biological changes in other sections of the body.

Some hormones including peptide and amino acid-derived hormones are water-soluble so they cannot cross the cell membrane. These hormones interact with cell-surface receptors. On the other hand, small and lipid-soluble, nonpolar hormones like steroid hormones and gas hormones can move across the plasma membrane and bind to intracellular hormone receptors.

Lipid-soluble hormones like steroid hormones can pass through the membrane of an endocrine cell. Outside the cell, these hormones bind to transport proteins which help them travel through the bloodstream.

Once they reach the target cell, the hormones separate from the transport proteins, diffuse through the plasma membrane, and bind to intracellular receptors in the cytoplasm or nucleus. In doing so, it activates the cell signaling pathways that regulate the transcription of specific genes in a cell’s DNA. The hormone-receptor complex regulates transcription by increasing or lowering the production of mRNA molecules from certain genes. This, in turn, alters the proteins synthesized during gene expression.

The nitric oxide (NO) / cyclic guanosine monosphosphate (cGMP) signaling pathway

The NO/cGMP pathway can be found in mature leukocytes and platelets. It consists of soluble guanylyl cyclase (GC) which functions as the intracellular receptor for nitric oxide.

When NO binds to GC, NO undergoes conformational change which activates the GC and converts guanosine triphosphate (GTP) to cGMP. The production of cGMP then triggers the activation of the cGMP-dependent protein kinase which, in turn, phosphorylates various substrates and participates in regulating the adhesion and aggregation of platelets.