Introduction

The ability of cells to communicate is crucial for maintaining cell function and homeostasis. Cells communicate through gap junctions, juxtacrine signaling, or secreted chemical messengers. Gap junctions enable the direct transfer of signaling molecules between the cytoplasm of 2 connected cells. Juxtacrine signaling involves a membrane-bound chemical messenger that directly interacts with a receptor on the plasma membrane of an adjacent cell.

Secreted chemical messengers are released from the originating cell and are classified into the following 4 types:

• Paracrine signaling molecules: target neighboring cells close to the release site. 
• Autocrine signaling molecules: target the same cell that secreted them. 
• Hormones: are released by endocrine cells and reach target cells in one or more distant body locations via blood circulation.
• Neurotransmitters: are released by neurons and affect other neurons or effector cells near the release site. 

Signal transduction begins when a chemical messenger, acting as a ligand, binds to a specific cellular receptor on the target cell. This binding induces a conformational change in the receptor, leading to its activation. Depending on the receptor type, a sequence of signaling events occurs, leading to specific responses such as altered gene expression, changes in cell morphology, modulation of proliferation or growth rate, and adjustments in metabolism.

Although cellular receptors primarily bind to endogenous ligands, 2 notable exceptions exist—pathogenic viruses, which can bind to host cellular receptors to infect a cell, and bacterial components, which can bind to receptors on immune cells to initiate an immune response.[1]

Cellular receptors can be either intracellular or cell surface proteins. Intracellular receptors that located in the cytoplasm or nucleus of target cells bind lipid-soluble chemical messengers. Cell surface receptors are transmembrane proteins that bind water-soluble chemical messengers. 

Cellular Level

Types of Chemical Messengers

Chemical messengers are classified as water-soluble (hydrophilic) or lipid-soluble (hydrophobic).

Hydrophobic chemical messengers include steroid hormones derived from cholesterol (eg, cortisol, testosterone, and estrogen), thyroid hormones, eicosanoids (eg, prostaglandins and leukotrienes), and gases (eg, nitric oxide). These messengers cross the cell membrane's lipid bilayer by simple diffusion and bind to intracellular receptors within target cells.

Hydrophilic chemical messengers include peptide hormones (eg, glucagon and growth hormones), amino acid neurotransmitters (eg, glycine and glutamate), amino acid derivative neurotransmitters (eg, epinephrine and norepinephrine), peptide neurotransmitters (eg, substance P), cytokines (eg, interleukins and interferons), growth factors (eg, epidermal growth factor [EGF] and fibroblast growth factor [FGF]), and nucleotides and nucleosides (eg, adenosine triphosphate [ATP], adenosine diphosphate [ADP], and adenosine). As these messengers cannot cross the lipid bilayer of cell membranes, they bind to cell surface receptors on target cells.

Intracellular Receptors

Intracellular receptors, also known as nuclear receptors, regulate cellular functions by altering gene expression. These receptors are classified into 2 types—type I and type II nuclear receptors.

Type I intracellular receptors: In the inactive state, type I nuclear receptors are found in the cytoplasm and are usually bound to a chaperone protein. Following the binding of a ligand, the receptor undergoes a conformational change that releases the chaperone protein and allows the receptor to translocate to the nucleus. Once in the nucleus, the ligand-receptor complex binds to a specific DNA sequence and acts as a transcription factor to modulate the transcription of one or more genes. Type I intracellular receptors include the glucocorticoid, androgen, and progesterone receptors.[2] 

Type II intracellular receptors: Type II intracellular receptors are located in the nucleus regardless of ligand-binding status. In the inactive state, these receptors are bound to co-repressor proteins. The co-repressor proteins are released upon ligand binding, allowing the receptor to bind to DNA and modulate gene expression. Type II intracellular receptors include retinoic acid and thyroid hormone receptors.[3]

Cell-Surface Receptors

Cell-surface receptors are transmembrane proteins embedded in the plasma membrane of target cells. These receptors consist of an extracellular domain containing the ligand-binding site, a transmembrane domain, and an intracellular domain that transmits the signal inside the cell. When a water-soluble ligand binds to a cell-surface receptor, it activates the receptor, initiating a signal transduction pathway that alters cellular function. The 3 types of cell-surface receptors include G protein–coupled receptors (GPCRs), ion channel receptors, and enzyme-linked receptors. 

G protein–coupled receptors: GPCRs are the largest family of cell surface receptors and are the target of around 30% of the drugs approved by the US Food and Drug Administration (FDA).[4] They are 7-pass transmembrane proteins with an intracellular domain coupled to a G protein. G proteins are heterotrimeric and comprise Gα-, Gβ-, and Gγ subunits. Gα is bound to guanosine diphosphate (GDP) in its inactive form and is also associated with the Gβ- and Gγ subunits.

The binding of a ligand to a GPCR activates the receptor, enabling it to catalyze the exchange of GDP to guanosine triphosphate (GTP) on the Gα subunit. This exchange activates the Gα subunit, causing it to dissociate from the Gβ and Gγ subunits, which remain together as a complex known as Gβγ. Both active Gα-GTP and Gβγ then activate their downstream targets to modulate cellular functions. Termination of GPCR signaling involves the hydrolysis of GTP to GDP by the intrinsic GTPase activity of the Gα subunit.[5] 

The effect of GPCR activation on a target cell depends on the specific G protein it is coupled with and the associated signaling pathway. G proteins are classified based on the type of Gα subunit they contain. The 4 types of Gα subunits correspond to 4 families of G proteins, as mentioned below.

• Gs (stimulatory) family: This activates adenylate cyclase, which catalyzes the conversion of ATP into cyclic adenosine monophosphate (cAMP). cAMP is a second messenger that activates protein kinase A (PKA), phosphorylating downstream target proteins. The effects of PKA activation depend on the cell type and available protein targets. 

• Gi (inhibitory) family: This inhibits adenylate cyclase, leading to decreased cAMP levels and PKA activity.

• Gq family: This activates phospholipase C, which catalyzes the hydrolysis of the membrane phospholipid called phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol triphosphate (IP3) and diacylglycerol. IP3 is a second messenger that diffuses through the cytoplasm to the endoplasmic reticulum, where it binds to IP3 receptors and releases Ca²⁺ ions from the endoplasmic reticulum into the cytoplasm. In addition, diacylglycerol, another second messenger, remains in the membrane and, along with the increased intracellular Ca²⁺, activates protein kinase C (PKC), which phosphorylates various target proteins to elicit cellular responses.

• G12/13 family: This activates Rho family GTPases, which regulate the cytoskeleton and control cell movement.

Examples of GPCRs include adrenergic receptors, muscarinic acetylcholine receptors, dopamine receptors, and opioid receptors.

Ion channel receptors: Ion channel receptors are ligand-gated ion channels that open upon ligand binding, allowing the passage of specific ions (eg, Na+, K+, Ca²+, or Cl-) across the plasma membrane. Examples of ion channel receptors include nicotinic acetylcholine receptors and gamma-aminobutyric acid (GABA) type A receptors. 

Enzyme-linked receptors: Enzyme-linked receptors either possess intrinsic enzymatic activity or activate an associated intracellular enzyme.

Most receptors with intrinsic enzymatic activity are receptor tyrosine kinases (RTKs). Ligand binding to an RTK induces dimerization and activation, leading to autophosphorylation on tyrosine residues. These phosphorylated tyrosine residues act as docking sites for intracellular signaling molecules, which in turn activate kinases and initiate signaling cascades. Examples of RTKs include insulin receptors and growth factor receptors, such as the EGF and FGF receptors.

Additional types of receptors with intrinsic enzymatic activity include protein tyrosine phosphatases, which remove phosphate from phosphotyrosine residues; protein-serine/threonine kinases, which add phosphate on serine or threonine residues; and guanylyl cyclases, which catalyze the formation of cyclic guanosine monophosphate (cGMP). 

Other enzyme-linked receptors lack intrinsic enzymatic activity but activate intracellular enzymes. After ligand binding and activation, most of these receptors directly activate a non-covalently associated cytoplasmic kinase. Most of these cytoplasmic kinases belong to the Src or Janus kinase (JAK) families of tyrosine kinases.  

Development

Embryonic development is a complex process that involves precise spatial and temporal regulation of cellular processes, including cell migration, differentiation, and proliferation. This process depends on coordinated and rapid cellular communication. Several chemical messengers, such as FGF, hedgehog proteins, Wnt, and transforming growth factor beta (TGF-β), are essential for proper embryonic development.[6] These messengers function by activating their respective cell surface receptors. 

FGF receptors are a family of RTKs that dimerize and autophosphorylate upon FGF binding.[6] Wnt binds to frizzled receptors (FZD), which are GPCRs, along with the co-receptors LRP5/6 (low-density lipoprotein [LDL] receptor–related proteins).[7] Hedgehog binds to patched (Ptch) receptors, which are 12-pass transmembrane proteins that regulate the activity of the Smoothened (Smo) receptor, which is a GPCR. Hedgehog binding to Ptch relieves its inhibition of Smo, allowing Smo to become active and initiate downstream signaling pathways, including the canonical β-catenin pathway and non-canonical pathways. TGF-β receptors are serine/threonine kinase receptors.[8] TGF-β binds to the TGF-β type II receptor, which then recruits and phosphorylates the TGF-β type I receptor. This activation leads to the phosphorylation and activation of SMAD proteins, which translocate to the nucleus to regulate gene expression.[9]

Signaling pathways activated downstream of FGF, Wnt, Hedgehog, and TGF-β are highly conserved and play crucial roles in coordinating the complex processes essential for proper vertebrate embryonic development. These processes include the formation and specification of germ layers and axis development.[6]

Organ Systems Involved

Regulation of body functions and maintenance of homeostasis depend on extensive and coordinated cell communication both within and between organ systems. Therefore, every organ system in the body relies on cellular receptors. This communication is crucial for a wide range of all body functions, including, but not limited to, development and growth coordination, proper immune responses, tissue repair and regeneration, neurotransmission, cellular processes such as cell cycle control and apoptosis, regulation of physiological parameters such as blood pressure, and the overall functioning of all organs. 

Pathophysiology

Several mechanisms can affect the function of cellular receptors, which could lead to dysregulation of associated signaling pathways and disease. The pathophysiology of cellular receptors involves changes in how ligands interact with receptors or in the receptors' own activity. These mechanisms include mutations affecting receptor function, overexpression, loss of expression, misfolding and degradation, altered trafficking, autoantibodies, ligand binding issues, receptor isoforms, and receptor cleavage. Additionally, certain viruses and bacteria can cause infectious diseases by hijacking the function of cellular receptors. 

Mutations Affecting Receptor Function

Point mutations, insertions, or deletions in the gene encoding a cellular receptor can alter the receptor's structure and function. These changes may result in either a dysfunctional receptor or one that is constitutively active.

Overexpression

Overexpression of cellular receptors occurs due to gene amplification, which increases the copy number of a receptor gene, or through overactivity of a gene promoter. This leads to upregulation of the signaling pathways associated with the receptor. 

Loss of Expression

Deletion of a cellular receptor gene results in the complete loss of expression. Epigenetic modifications, such as methylation and histone modification, can also silence a receptor gene, leading to reduced expression. This loss of expression leads to loss of function and downregulation of signaling pathways. 

Misfolding and Degradation

Mutations in a receptor gene, errors in posttranslational modifications, or environmental factors (eg, oxidative stress) can lead to misfolding of cellular receptors. Misfolded receptors are typically retained in the endoplasmic reticulum and are often targeted for degradation. 

The normal physiology of cellular receptors involves regulatory turnover, whereby receptors that are no longer needed or are part of a signaling pathway that needs to be terminated are ubiquitinated and targeted for degradation by the proteasome. This process can also be triggered by specific signals that modulate signaling pathways. However, dysregulation of this degradation pathway can lead to abnormal downregulation of cellular receptors and contribute to disease.

Altered Trafficking

The proper functioning of cellular receptors requires them to be appropriately located within the cell, which is accomplished by cellular trafficking. For example, cell surface receptors must be transported from the rough endoplasmic reticulum to the Golgi apparatus and then to the membrane of a secretory vesicle, which subsequently fuses with the plasma membrane to insert the receptor. Defective trafficking can lead to reduced receptor numbers on the plasma membrane. This can result from defects in the cellular receptor itself, such as mutations or inappropriate posttranslational modifications; defects in the cellular trafficking machinery, including mutations in trafficking proteins or disruption of the cytoskeleton; disruption of protein-protein interactions, either between the receptor and chaperone proteins or with other proteins necessary for proper trafficking; environmental factors like nutrient availability; and infectious agents, such as viruses that hijack the cell's trafficking machinery.

Autoantibodies

In certain autoimmune disorders, autoantibodies target cellular receptors. The binding of these autoantibodies can block the binding of the endogenous ligand or alter the receptor's conformation, leading to its inhibition. Conversely, autoantibodies can also inappropriately activate a receptor, resulting in abnormal upregulation of the associated signaling pathway. 

Ligand Binding Issues

Mutations can change the receptor's binding affinity for its ligand, either increasing or decreasing it, leading to altered signaling. Additionally, competitive inhibition by other molecules that bind to the receptor's ligand-binding site may prevent normal ligand binding and receptor activation.

Receptor Isoforms and Cleavage

Aberrant gene splicing can produce dysfunctional receptor isoforms. Some of these isoforms may form heterodimers with normal receptors, creating a dominant negative effect that impairs receptor function. Similarly, abnormal proteolytic cleavage of receptors can generate dysfunctional fragments that either lack signaling capability or exhibit altered functions.

Infectious Diseases

The pathophysiology of infectious diseases often involves hijacking cellular receptors or altering their function. For example, viruses frequently gain entry into host cells by binding to specific cellular receptors. Similarly, some bacterial toxins target specific receptors to exert their effects.

Clinical Significance

Dysregulation of cellular receptors and their associated signaling pathways, through one of the mechanisms described earlier, can lead to various human disorders. These include cancer, cardiovascular diseases, neurological disorders, metabolic and endocrine disorders, autoimmune diseases, and infectious diseases.

Cancer

Cellular receptors are crucial in regulating cell proliferation, growth, and apoptosis by activating signaling pathways. Disruption of these pathways can lead to uncontrolled growth, evasion of apoptosis, and other cancer hallmarks. This disruption can occur through various mechanisms, including receptor overexpression and subsequent upregulation of associated signaling pathways, mutations causing constitutive receptor activation in the absence of a ligand, gene amplification leading to increased receptor density on the cell surface, upregulation of autocrine or paracrine signaling where cancer cells secrete excessive growth factors that act on themselves or neighboring cells, epigenetic modifications resulting in receptor overexpression or loss of negative regulation, and defective receptor internalization that prolongs and sustains signaling.

Cardiovascular Diseases

Dysregulation of cellular receptors contributes significantly to the development and progression of cardiovascular diseases such as hypertension, heart failure, atherosclerosis, coronary artery disease, and arrhythmias. For example, chronic activation of beta-1 adrenergic receptors elevates heart rate and contractility, which can lead to hypertension and increase the risk of arrhythmias.

On the other hand, downregulation or desensitization of beta-1 adrenergic receptors can impair cardiac function and contribute to the progression of heart failure.[10] Overactivation of angiotensin II receptors (AT1R) leads to vasoconstriction and increased blood volume, which could result in hypertension.[11] Dysregulation of endothelin receptors increases vascular tone, which contributes to atherosclerosis and coronary artery diseases.[12] Abnormal activation of platelet receptors (such as P2Y12, which is a GPCR) can lead to platelet activation and aggregation, abnormal clot formation, and acute coronary syndrome.[13] 

Neurological Diseases

Signaling initiated by neurotransmitters binding to their receptors is crucial for neurotransmission and maintaining proper communication and function of neurons and glial cells. Dysregulation of these receptors can alter neurotransmission, synaptic plasticity, neuronal survival, and inflammatory responses, contributing to the manifestation of neurological symptoms and the development of neurological disorders. Examples are provided below.

N-methyl-D-aspartate receptor: N-methyl-D-aspartate receptors (NMDARs) are glutamate receptors that have a key role in synaptic plasticity and memory formation. Dysregulation of NMDAR activity, whether through excessive activation or inhibition, contributes to various neurological and psychological disorders. Hyperactivation of NMDARs leads to excitotoxicity, which plays a role in epilepsy, Huntington disease, and Parkinson disease. In contrast, hypoactivation of NMDARs is associated with cognitive dysfunction and psychotic symptoms in schizophrenia.[14]

Dopamine receptors: Dopamine receptors, especially D1 and D2, play a crucial role in regulating motor control, reward pathways, and cognition. In Parkinson disease, the loss of dopaminergic neurons reduces dopamine signaling through these receptors, leading to motor dysfunction.[15] In schizophrenia, dysregulation of dopamine receptor signaling, especially hyperactivation of D2 receptors, is linked to positive symptoms such as hallucinations and delusions.[16] 

GABA receptors: GABA receptors are the primary inhibitory receptors in the brain, and they are responsible for reducing neuronal excitability. Dysregulation of GABAergic signaling, including mutations in GABA receptor subunits or altered receptor expression, can disrupt the balance between excitation and inhibition, contributing to the development of epilepsy and anxiety disorders.[17] 

Nerve growth factor receptor: TrkA, a receptor for nerve growth factor (NGF), is crucial for the survival and function of specific neurons, particularly in the peripheral nervous system. Mutations or dysregulation of TrkA can result in autonomic neuropathies, where patients experience severe sensory and autonomic dysfunction due to the loss of NGF-mediated neuronal support.[18]

Endocrine and Metabolic Disorders

Hormones regulate metabolism, growth, reproduction, and homeostasis by binding to their cellular receptors. Dysregulation of these receptors disrupts normal hormonal signaling pathways, leading to excessive or insufficient hormonal responses. This imbalance contributes to various endocrine and metabolic disorders, as illustrated by the examples below.

Type 2 diabetes: The insulin receptor is critical for glucose uptake in response to insulin. In type 2 diabetes, insulin resistance arises from decreased sensitivity of the insulin receptor or defects in post-receptor signaling. This results in impaired glucose uptake, hyperglycemia, and, eventually, the development of diabetes. Furthermore, mutations in the insulin receptor can cause severe insulin resistance syndromes, such as Donohue syndrome (leprechaunism).[19] 

Graves Disease and congenital hypothyroidism: The thyroid-stimulating hormone receptor (TSHR) is essential for the synthesis and release of thyroid hormones. In Graves disease, an autoimmune disorder, antibodies mimic TSH and bind to the TSH receptor, leading to hyperthyroidism.[20] Conversely, mutations in the TSHR gene can cause congenital hypothyroidism, where impaired receptor function results in inadequate TSH production.[21] 

Hyperparathyroidism and pseudohypoparathyroidism: The parathyroid hormone receptor (PTHR), primarily PTHR1, is crucial for calcium homeostasis. In hyperparathyroidism, whether due to parathyroid adenomas or secondary causes, excessive activation of PTHR1 leads to increased calcium release from bones, enhanced kidney calcium reabsorption, and hypercalcemia. In pseudohypoparathyroidism, mutations in the Gαs subunit impair PTHR1 signaling, resulting in resistance to PTH and leading to hypocalcemia and hyperphosphatemia despite elevated PTH levels.

Androgen insensitivity syndrome: The androgen receptor (AR) mediates the effects of androgens such as testosterone. In androgen insensitivity syndrome, mutations in the AR gene cause varying degrees of resistance to androgens. This results in a spectrum of phenotypes, ranging from complete development of female external genitalia to mild infertility in males.[22]  

McCune-Albright syndrome: This syndrome is caused by a somatic mutation in the GNAS gene, which encodes the Gαs subunit of Gs proteins. The mutation leads to constitutive activation of Gαs, resulting in increased cAMP production and excessive activation of downstream signaling pathways, which is independent of GPCR activation. Symptoms include light brown, irregularly shaped skin lesions (café-au-lait spots), precocious puberty, and fibrous dysplasia. The syndrome may also present with hyperthyroidism, Cushing syndrome, and either gigantism or acromegaly.[23] 

Cushing syndrome and glucocorticoid resistance: The glucocorticoid receptor mediates the effects of glucocorticoids such as cortisol, which are involved in stress responses, metabolism, and immune regulation. In Cushing syndrome, excessive activation of the glucocorticoid receptor, often due to prolonged exposure to high cortisol levels, leads to symptoms such as obesity, hypertension, and insulin resistance. Conversely, glucocorticoid resistance, caused by mutations in the gene encoding the glucocorticoid receptor, results in a reduced response to cortisol.

Familial hypercholesterolemia: The LDL receptor is responsible for clearing LDL cholesterol from the bloodstream. In familial hypercholesterolemia, mutations in the LDL receptor gene result in reduced function or expression of LDL receptors, leading to elevated LDL cholesterol levels. This dysregulation contributes to the development of atherosclerosis and increases the risk of cardiovascular disease.[24]

Autoimmune Diseases

Dysregulation of cytokine receptors can lead to inappropriate immune responses. For example, upregulation of the tumor necrosis factor-alpha (TNF-α) receptor is associated with rheumatoid arthritis and inflammatory bowel disease. Additionally, abnormal activation of T-cell receptors plays a role in various autoimmune diseases, including rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus.

Myasthenia gravis is an autoimmune disease characterized by symptoms such as muscle weakness, fatigue, drooping of the eyelid (ptosis), double vision (diplopia), and difficulty swallowing. These symptoms tend to worsen progressively, fluctuate in severity, and improve with rest. Approximately 80% of patients with myasthenia gravis produce autoantibodies against nicotinic acetylcholine receptors, which are ligand-gated ion channel receptors located on the surface of skeletal muscle cells at the neuromuscular junction. These receptors are crucial for muscle contraction.[25]  

Infectious Diseases

Viruses often bind to cell-surface receptors on host cells to gain entry, effectively hijacking these receptors for their own purposes. For instance, the HIV surface protein GP-120 must bind to the CCR5 receptor to enter human macrophages.[26] Individuals who are homozygous for a deletion in the CCR5 receptor are resistant to HIV strains that rely on this receptor for infection. Research is also exploring strategies to target and block the CCR5 receptor as a means to prevent HIV infection.[27] 

The influenza virus infects epithelial cells in the upper and lower respiratory tracts. The viral surface protein hemagglutinin binds to sialic acid, a sugar found on the cell surface. The influenza virus binds to sialic acid, which acts as a cell receptor necessary for the virus to infect the cell.[28] Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, binds to angiotensin-converting enzyme 2 (ACE2) and the type II transmembrane serine protease (TMPRSS2) coreceptor to enter host cells.[29] 

Genetic Disorders

Inherited gain-of-function or loss-of-function mutations in genes coding cellular receptors can lead to genetic disorders, as mentioned below.

Achondroplasia: An autosomal dominant genetic disorder caused by a gain-of-function mutation in FGF receptor-3 (FGFR3). FGFR3 is an RTK that is highly expressed in chondrocytes, particularly in the growth plate of developing bones. Infants with achondroplasia generally present with short limbs and digits, a saddle nose deformity, and a large head.

Familial hypercholesterolemia: An autosomal dominant genetic disorder caused by a loss-of-function mutation in the LDL receptor. The LDL receptor plays a key role in clearing low-density lipoprotein (LDL) cholesterol from the bloodstream. In familial hypercholesterolemia, non-functional LDL receptors result in decreased LDL clearance, leading to elevated blood cholesterol levels and an increased risk of cardiovascular disease.[24]