Introduction

Cellular receptors are proteins either inside a cell or on its surface that receive a signal. This is a chemical signal in normal physiology where a protein ligand binds a protein receptor. The ligand is a chemical messenger released by 1 cell to signal itself or a different cell. The binding results in a cellular effect, which manifests as any number of changes in that cell, including altering gene transcription or translation or changing cell morphology. Typically, a single ligand has a single receptor to which it can bind and cause a cellular response. There are several different types of cellular signaling, all of which depend on other ligands and cellular receptors.

The major categories of cellular signaling include:

• Autocrine: A cell releases a signal that binds 1 of its receptors to change its functioning
• Signal across a gap junction: Small signaling molecules move directly across neighboring attached cells
• Paracrine: Communication between cells that are nearby
• Endocrine: Cell signals travel through the bloodstream to target cell receptors in different parts of the body

Each type of signaling requires a ligand and a receptor. Cellular receptors can broadly be categorized into internal, cell-surface, ion channel, G-protein-coupled (GPCRs), and enzyme-linked receptors. Although most cell receptor binding is by a chemical ligand, 2 notable exceptions are pathogenic viruses that can bind host cellular receptors to infect a cell and bacterial components, which can bind receptors on immune cells to cause an immune response.[1]

Cellular Level

Types of Ligands

Ligands are the signaling molecules the body uses for various cells to communicate with other cells. The adrenal gland can release a hormone such as cortisol, which shares with a large variety of different cells of different organs to have a significant effect, or 1 inhibitory neuron can release a neurotransmitter like γ-aminobutyric acid (GABA) to exert a straightforward impact on another cell. The effect of the ligand is dependent on both the ligand itself and the receptor it targets. For example, small and hydrophobic ligands such as steroids like cortisol often target internal receptors as they can pass through the plasma membrane without help. On the other hand, large or hydrophilic ligands such as GABA cannot pass through the cell membrane and must target cell surface receptors. 

Internal Receptors

These receptors are also known as either intracellular or cytoplasmic. They are found in the cytoplasm of a cell and are often targeted by hydrophobic ligands that can cross the lipid bilayer of the animal plasma cell membrane. Often, these receptors act to modify messenger RNA (mRNA) synthesis and, thus, protein synthesis within the cell. They accomplish this by the ligand-receptor complex traveling to the nucleus and binding DNA at a gene regulatory site, which the receptor and ligand on their own would be unable to do. Testosterone, estrogen, cortisol, and aldosterone are examples of hydrophobic steroid hormones that pass through the plasma membrane to target internal receptors. Internal receptors often work without needing second messengers to relay the signal before mRNA synthesis and protein synthesis are affected, a process unique to internal receptors, as other types work through a cellular cascade that alters protein synthesis.

Cell-Surface Receptors

These receptors are also known as transmembrane receptors. These proteins are found on the surface of cells and span the plasma membrane. They bind to ligands that cannot pass through the plasma membrane by themselves. These are often hydrophilic ligands or ones too large to make it through. These receptors don't bind DNA to modify gene transcription and translation but rather perform signal transduction; an extracellular signal triggers an intracellular signal, which usually goes to the nucleus to affect cell functioning. Often, a cell surface receptor is specific for that cell type so that the ligand can only affect the functioning of its target cells. The components of a cell surface receptor can break down into an external ligand-binding domain, a hydrophobic region that spans the membrane, and an intracellular domain that is responsible for starting a second messenger cascade. Cell-surface receptors come in 3 main types: ion channel receptors, GPCRs, and enzyme-linked receptors.

Ion Channel Receptors

When a ligand binds an ion channel receptor, a channel through the plasma membrane opens, allowing specific ions to pass through. This process requires a specialized membrane-spanning region of the receptor. Ligand binding changes the receptor's shape, allowing specific ions, usually sodium, magnesium, calcium, or hydrogen, to pass. Chemically gated ion channels are on dendrites and the cell bodies of neurons.

GPCRs

GPCRs are a subtype of cell surface receptors that act through a G-protein to start a second messenger cascade, modulating cellular function. The receptor has a ligand-binding site outside the plasma membrane and a transmembrane portion that can bind to a G-protein in the intracellular space. A G-protein is a heterotrimeric protein with 3 subunits: alpha, beta, and gamma. The beta and gamma subunits are attached to the membrane by a lipid anchor. When no ligand is bound to the receptor, the alpha subunit and a guanosine diphosphate (GDP) are bound to the transmembrane receptor and the beta and gamma subunits. When the ligand binds to the receptor, a conformational change activates the G protein, and a guanosine triphosphate (GTP) molecule replaces the GDP molecule on the alpha subunit.

The G-protein dissociates with the beta and gamma subunits remaining attached by their anchor, and the activated alpha subunit, now bound to a GTP molecule, is freed from the intracellular wall of the plasma membrane. Both the beta-gamma dimer and the alpha-GTP can act to propagate the signal cascade. Some common enzymes and second messengers activated by this cascade include adenylate cyclase, cyclic adenosine monophosphate AMP, diacylglycerol, inositol 1, 4, 5-triphosphate, and phospholipase C. GPCRs can be both activating and inhibiting. GPCRs are involved in many functions of the multicellular organism, including but not limited to growth, endocrine signaling, sensation, and clotting.

Enzyme-Linked Receptors

This subtype of transmembrane receptors has a catalytic site on the cytoplasmic domain. When the ligand binds these receptors, they often dimerize, activating the receptor's catalytic site and resulting in enzymatic activity. There are several types of enzyme-linked receptors; the most common type is the receptor tyrosine kinase. Other examples include receptor serine/threonine kinase, receptor guanylyl cyclase, and receptor tyrosine phosphatases. Receptor tyrosine and receptor serine and threonine kinases dimerize, which causes autophosphorylation to happen at the tyrosine, serine, or threonine sites, respectively. This phosphorylation is what activates the enzymatic activity of the receptor. Many growth signals, such as epidermal and platelet-derived growth factors, work with a receptor tyrosine kinase.

Development

A single cell becoming a complex multicellular organism requires careful regulation of cellular activities, including differentiation, migration, and proliferation. All of these actions must happen at the correct time and place. This high level of coordination requires extensive, coordinated, and fast-acting cellular communication. Several key signaling pathways are identified in human and animal studies needed for proper development, including FGF, hedgehog, Wnt, TGF beta, and notch. One ligand can bind several different receptors on different cells to cause other downstream effects. For example, the ligand can bind multiple receptor complexes in the Wnt pathway and trigger several downstream signaling cascades, resulting in diverse cellular responses. This is 1 example of how cellular receptors can turn the same signal into several different effects. A single cell develops into a complex multicellular organism at the correct time relative to other cellular processes through the complex interaction of ligands and receptors.

Organ Systems Involved

Every organ system in the body requires cellular communication and, thus, cellular receptors, including cell-cell interactions like macrophages activating plasma cells of the immune system and the acetylcholine release at the neuromuscular junction of the nervous system. This activity also includes body-wide interactions like the hypothalamic release of ectopic adrenocorticotropic hormone (ACTH), causing the adrenal release of cortisol, affecting almost every organ system. Ultimately, the ability of any organism to become multicellular relies on the ability to use cellular receptors for communication.

Pathophysiology

There are 2 main ways cellular receptors are involved with human pathophysiology: microorganisms binding human cell receptors for survival or resulting in disease and cellular receptor dysfunction resulting in the failure of normal physiologic processes, which results in disease.

Viruses must bind to cell-surface receptors on the host cell to gain access. In this way, viruses have hijacked human cell receptors for their use. For example, the HIV surface protein GP-120 must bind to the CCR5 receptor to enter human macrophages.[2] People homozygous for a deletion in the CCR5 receptor are resistant to infection from HIV viruses that need this receptor for infection. Also, research is underway to target the CCR5 receptor to block HIV infection.[3]

The influenza virus infects the epithelial cells of the upper and lower respiratory tract. The virus cells have a protein on their surface called hemagglutinin, which binds to sialic acid. Sialic acid is a sugar found on the cell surface. By the virus binding sialic acid, the sugar acts as a cell receptor for influenza, which is necessary for the virus to infect a cell.[4] Some conditions caused by a defect in a cell receptor include:

Pseudohypoparathyroidism

Pseudohypoparathyroidism refers to a heterogeneous group of disorders defined by target organ unresponsiveness to parathyroid hormone (PTH). This condition is due to any dysfunction in the PTH signaling pathway. One specific cause for pseudohypoparathyroidism is a missense mutation in the PTH gene sequence, which results in reduced PTH-receptor binding.[5] When the signal cannot bind to its receptor, PTH cannot act at its various target organs, specifically the kidneys, and bones, to regulate calcium and phosphorus levels in the body.

McCune-Albright Syndrome 

McCune-Albright syndrome is a rare disorder that presents with the triad of peripheral precocious puberty, café-au-lait spots, and fibrous dysplasia of bone. Children with McCune-Albright syndrome have a somatic mutation of the alpha subunit of a stimulatory G protein, which activates adenylyl cyclase. The mutation in this protein results in continued stimulation of its signaling cascade regardless of receptor binding.[6]

Familial Hypercholesterolemia

The American Heart Association criteria for the clinical diagnosis of familial hypercholesterolemia is a low-density lipoprotein (LDL) level above 190 mg/dl and either a first-degree relative with an LDL level above 190 mg/dl or known premature coronary heart disease. In about 80% of patients with confirmed familial hypercholesterolemia, there is a mutation in 1 of 3 genes involved with LDL-receptor-mediated LDL catabolism. Of the 80% with a known mutation, 85 to 90% of the mutations are in the LDL receptor. The most common etiology of FH is a mutation in the apo B/E cellular receptor for LDL. Typically, LDL particles bind to the LDL receptor on hepatic cell surfaces. When these LDL particles are attached, they are internalized and catabolized, removing them from the blood. Researchers have identified over 1600 different mutations in the LDL receptor, resulting in 4 classes of alleles based on the mutant receptor's resulting phenotype.[6]

• Class I: Protein is not synthesized
• Class II: Intracellular transport of receptors from the endoplasmic reticulum to the Golgi is impaired
• Class III: The receptor makes it to the cell's surface but cannot bind to LDL.
• Class IV: The LDL binds normally, but the receptors do not cluster in coated pits, and LDL particles do not become adequately internalized.

Regardless of the classes, when someone does not have a properly functioning LDL receptor, they cannot correctly clear LDL from their blood. The result is early-onset atherosclerosis and associated pathology.

Myasthenia Gravis

Myasthenia gravis is a disease that often presents in the second and third decades of life with a female predominance or the sixth to eighth decades of life with a male predominance. The most common feature of myasthenia gravis is fluctuating muscle weakness. The disease results from autoantibodies against the acetylcholine receptor.[7] These antibodies act at the neuromuscular junction and block acetylcholine from binding to its cellular receptor. Also, the binding of the autoantibodies causes the cross-linking and internalization of the receptors. When acetylcholine cannot bind to most of its cellular receptors in the neuromuscular junction, the muscle cannot contract as well as it should.

Androgen Insensitivity Syndrome

Androgen insensitivity syndrome is a condition affecting sexual development both before birth and during puberty. When a fetus is genetically male, with an X and a Y chromosome, the fetus should develop as a male and undergo male changes during puberty. During development, the fetus develops internal male organs due to the SRY gene on the Y chromosome. Still, without androgen signaling, the external phenotype of the patient is female. This is the state in patients with androgen insensitivity syndrome as they have a loss-of-function mutation in the gene that encodes for the androgen receptor.[8] Without this receptor, androgen levels are normal or high but do not affect development.

Achondroplasia 

Achondroplasia is an autosomal dominant condition and the most common bone dysplasia in humans. Patients with achondroplasia have a gain-of-function mutation in the FGFR3 gene, which results in a permanently activated FGFR3 receptor.[9] This receptor does not need to have its ligand bound to become activated. As a result, chondrocyte proliferation becomes inhibited and endochondral bone formation impaired, which results in growth restriction and bone shortening, among other skeletal abnormalities.[10]

Clinical Significance

Bacterial sepsis and the resulting septic shock result from the overproduction of inflammatory signals. This overproduction of inflammatory signals results from the immune system's interaction with bacterial wall constituents. Lipopolysaccharides, peptidoglycans, and others are particularly implicated in this process. When these bacterial wall components bind to complement and Fc receptors on the surface of mononuclear cells, the macrophage becomes metabolically active, produces microbicidal agents, and secretes proinflammatory cytokines such as tumor necrosis factor-alfa (TNF-alpha).

Pseudohypoparathyroidism

Patients with pseudohypoparathyroidism can be hypocalcemic, hyperphosphatemic, and have elevated PTH as the parathyroid gland tries to make more hormones to fix the imbalances. Patients with pseudohypoparathyroidism can have their electrolyte imbalances manifest as tetany, seizures, cardiac arrhythmias, papilledema, and psychiatric symptoms.

McCune-Albright Syndrome

In patients with McCune-Albright syndrome, endocrine functions are most affected, resulting in precocious puberty, thyrotoxicosis, gigantism, acromegaly, Cushing syndrome, or hypophosphatemic rickets, depending on where the mutation occurred. Mutations can also occur in the liver or heart, resulting in cholestasis and hepatitis or cardiac arrhythmias.

Myasthenia Gravis

In patients with myasthenia gravis, often the first noticed symptom is diplopia or ptosis due to weakness of the ocular muscles or eyelid muscles. In worse forms of the disease, the bulbar, limb, and respiratory muscles can also be affected. A similar condition is Lambert-Eaton, where autoantibodies target the presynaptic calcium channels, resulting in the inability of the neuron to release acetylcholine into the NMJ.[7] Both of these conditions are due to the cells' inability to attach acetylcholine to their cellular receptor.

Androgen Insensitivity Syndrome

Androgen insensitivity syndrome exists on a spectrum, from partial to complete, based on the level of functioning of the androgen receptor. In complete androgen insensitivity, the presentation is often a healthy female child found to have inguinal masses that contain testes. Patients are also commonly identified during puberty when they fail to menstruate. Upon testing, patients have abnormally high levels of testosterone, LH, and FSH due to the failure of the negative feedback loop in the hypothalamic-pituitary-gonadal axis.

Achondroplasia

The mutation in achondroplasia causing a constitutively active FGF3 receptor inhibits chondrocyte proliferation and endochondral bone formation, resulting in growth restriction and bone shortening, among other skeletal abnormalities.[10]