Introduction

Cellular communication is a complex process involving various biochemical steps and many different messenger molecules between cells and organs.[1] Cells in the human body are highly specialized, and they use various signaling mechanisms to perform different functions. Paracrine signaling is a mechanism in which one cell secretes a molecule that acts on a second cell in close proximity. The signaling molecule may never enter the bloodstream. In contrast, endocrine signaling involves the secretion of a molecule by one cell into the bloodstream. The signaling molecule can travel in the blood and bind to the receptor on the effector cell. Autocrine pathway functions by the secretion and reception of a messenger molecule by a single cell. Juxtacrine signaling is a form of cell communication by direct contact. All these signals influence the behavior of the effector cells. These behaviors include regulating physiologic processes such as metabolism, transport, motility, division, and growth.[2]

The interaction between a messenger molecule and the target cell is just the beginning of a complex cascade of events that happens intracellularly. Most cellular messengers exert their effect through the interaction with a specific receptor coupled to the lipid membrane. There are also intracellular receptors that interact with lipophilic molecules that diffuse through the lipid membrane in both directions without the help of transport proteins.

Examples of cellular messengers are[3][4][5][6][7]: 

• Extracellular messengers: cytokines, autacoids, hormones, growth factors, catecholamines, histamine, serotonin, neurotransmitters, eicosanoids, nucleotides, and extracellular vesicles
• Intracellular messengers: cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate, calcium, phosphatidylinositols, nitric oxide (NO), and diacylglycerol

Cellular Level

When the cell undergoes stimulation by a messenger molecule, it elicits a cellular response. This response is due to the interaction between a ligand (messenger) and a specific receptor to that ligand. Almost all messengers interact with cell surface receptors, but there exist exceptions. For example, steroid hormones interact with intracellular (nuclear) receptors.[8] Examples of cell membrane receptors include G-protein-coupled receptors (GPCR) and receptor tyrosine kinase (RTK). Both are well studied and are targets of many pharmaceuticals.

The GPCR is the largest class of membrane coupled receptors, composed of a seven-transmembrane segment and a heterotrimeric G protein. Ligands of GPCR can be light, ions, or complex proteins.[9] The ligand-binding site of GPCRs is located on extracellular surface membranes. The intracellular surface interacts with heterotrimeric G proteins. G proteins have three subunits (alpha, beta, and gamma). When ligand interacts with specific GPCR, heterotrimeric G protein dissociates into alpha subunit and beta-gamma dimer. The alpha subunit is classified into three categories based on its function: Gs, Gi, and Gq. The Gs alpha subunit leads to the stimulation of the enzyme adenylyl cyclase. Adenylyl cyclase converts ATP to cyclic adenosine monophosphate (cAMP). The cAMP is a second messenger that activates protein kinase A and also interacts with other effector molecules. The Gi alpha subunit inhibits adenylyl cyclase. It results in cAMP depletion due to the tonic phosphodiesterase activity. The Gq alpha subunit activates the phospholipase C (PLC). PLC cleaves phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). These molecules act as second messengers. IP3 causes calcium release from the endoplasmic reticulum, and DAG activates protein kinase C. Protein kinase C can phosphorylate many other proteins.[10] 

The RTK are usually single transmembrane polypeptide chains with an intracellular tyrosine kinase domain; RTKs are involved widely in embryonic development and play essential roles in cell growth and proliferation. Examples of RTKs are insulin receptor, vascular endothelial growth factor receptor, nerve growth factor receptor, and fibroblast growth factor receptor.[11]

Intracellular receptors are located in the cytoplasm or within the nucleus. Glucocorticoids have receptors in the cytosol. It binds to the receptor and hormone-receptor complex then migrates into the nucleus to modify gene expression. Thyroid hormone receptors are intranuclear. Thyroid hormones enter the nucleus, bind to the receptor attached to the DNA, and modify gene expression. For the receptor to be intracellular, the messenger molecule needs to be lipophilic. Intracellular receptors also include the IP3 receptor on the endoplasmic reticulum. IP3 receptor activation causes the mobilization of calcium stores from the endoplasmic reticulum.

Development

Embryonic development is a complex process requiring billions of cells to function in unison to form a single living organism. This intricate process necessitates all of these cells to communicate with one another. Many signaling pathways are involved in this dynamic process. Studies have shown that proteins expressed by the WNT gene family are important messengers involved in embryonic development, cell migration, cell fate determination, and cell polarity. These genes are code for glycoproteins that interact with specific types of GPCRs: the frizzled receptors.[12]

Organ Systems Involved

Multiple organ systems are involved in cellular communication. Some of these organ systems are listed here[13][14]:

• Endocrine organs: Examples of endocrine organs include the thyroid gland, adrenal glands, pancreas, and pituitary gland; these organs use a hematogenous spread of hormones to transmit signals to target cells far away.

• Nervous system: The synapsis between neurons or in the neuromuscular junction is a type of paracrine signaling. A neuron releases a neurotransmitter in the synaptic cleft, and nearby cells (other neurons or muscle cells) receive signals through receptors to neurotransmitters. 

• Immune cells: Some immune cells release ATP during activation. ATP interacts with purinergic receptors in the same cell that secrete it via autocrine signaling. Immune cells also use juxtacrine signaling for antigen presentation and hemostasis. Cytokines are short-lived signaling molecules involved in immune system regulation. They can function in an endocrine, paracrine, or autocrine fashion.

Function

There are three types of cell-surface receptors: GPCR, enzyme-linked receptors, ligand-gated ion channels.

G protein-coupled receptors functions depend on the three elements: receptor, G-protein, and the effector molecule. The receptor has seven transmembrane helices and binds to the ligand on the extracellular regions. The intracellular binding domain binds to the G-protein. Activation of G-protein leads to the effector molecules that have various functions. Examples of ligands for GPCR include catecholamines, ACTH, LH, FSH, TSH, vasopressin, dopamine, and glucagon.

The receptor type and their connected G proteins are listed below:

• Sympathetic alpha receptors: alpha1 is Gq and alpha2 is Gi
• Sympathetic beta receptors: beta1, beta2, and beta3 are all Gs
• Parasympathetic muscarinergic: M1 and M3 are Gq, M2 is Gi
• Histamine: H1 is Gq and H2 is Gs
• Dopamine: D1 is Gs, D2 is Gi
• Vasopressin: V1 is Gq, V2 is Gs

Receptor tyrosine kinases are transmembrane receptors with tyrosine kinase activity. They are activated when ligand causes dimerization and autophosphorylation of the tyrosine residues of the cytoplasmic domain. Ligands for these receptors include insulin and growth factors. Effectors associated with tyrosine kinase receptors are phospholipase C (part of the IP3/DAG pathway, which cleaves PIP2 into IP3 and DAG) and Ras. Ras activates other signal transduction pathways like MAP (mitogen-activated protein) kinase that are needed for cell growth and proliferation.

Non-receptor tyrosine kinases do not have tyrosine kinase activity. Their ligands include growth hormones, interferons, prolactin, erythropoietin, and thrombopoietin. Janus kinase (JAK) family are separate tyrosine kinase proteins that are coupled with the receptor. Activation of the receptor leads to activation of STAT proteins that act as transcription factors for JAK-STAT regulated genes.

Receptor serine/threonine kinase bind to transforming growth factor-beta (TGF-beta).

Mechanism

The mechanism by which cellular messengers transmit a signal has three components: secretion of messengers molecule, distribution in different tissues, and interaction with the specific cell surface or intracellular receptors in the target cell.[15] There are four types of signaling based on the distance traveled by the messenger molecule.

Endocrine signaling: Hormones are signaling molecules that travel in the bloodstream throughout the body to reach the specific receptor on the membrane of the effector cell or bind to the receptor intracellularly. Long-range signaling is also is called endocrine signaling. Hormones of the endocrine system are the best example of long-range signaling. For example, epinephrine is secreted by the adrenal medulla into the blood. In the bloodstream, it can interact with many receptors (alpha and beta-adrenergic receptors). These receptors are distributed in several tissues, including the heart, blood vessels, lungs, liver, and kidneys. Adrenoceptors belong to the GPCR superfamily and divide into alpha and beta. Further subdivided as alpha-1, alpha-2, beta-1, beta-2 and beta-3. They regulate several physiological processes, like blood pressure, heart rate, and vasoconstriction. Another example is the hormone erythropoietin, secreted by specialized cells in the kidney. It stimulates erythroid progenitor cells in the bone marrow to produce more erythrocytes (erythropoiesis).[16]

Paracrine signaling: Paracrine signaling involves a cell secreting a molecule into the blood or the lumen. The signaling molecule can diffuse over a short distance and bind to the cells. An example of paracrine signaling is neurotransmission. The presynaptic neuron releases a neurotransmitter into the synaptic cleft and immediately interacts with a postsynaptic neuron.

Autocrine signaling: Autocrine signaling occurs when a cell secretes a signaling molecule binds to a receptor on the same cell. An example of autocrine signaling is IL-1 secreted by macrophages that bind to IL-1 receptors on the same cells.

Juxtacrine signaling: Juxtacine signaling involves the contact of two cells. This type of signaling is important in the immune system for antigen presentation. [17] Neutrophil extravasation is another example of juxtacrine signaling between endothelial cells and the neutrophil.

Pathophysiology

Disruption of cell communication or signaling can lead to pathologic states. For example, Graves disease is an autoimmune disease with antibodies (autoantibodies) directed against the thyroid-stimulating hormone receptors. Autoantibody and TSH receptor binding results in the production and release of thyroid hormones. Under physiological circumstances, TSH activates the TSH receptor, leading to the production and secretion of triiodothyronine (T3) and thyroxine (T4). In Graves disease, an excess of these hormones causes tachycardia, hyperreflexia, fine resting tremor, exophthalmos, and pretibial myxedema. Autoantibody also stimulates the growth and proliferation of thyroid-producing cells leading to diffuse goiter.[18]

Clinical Significance

Disturbances that increase or decrease the production of cellular messengers, hormones in this case, usually lead to pathologic states that affect many organs and systems because of their pleiotropic effects throughout the body; at the cellular level, hormones can affect cell division, differentiation, migration, and apoptosis. On a more complex level that comprises organs and systems, hormones can regulate blood pressure, glucose levels, digestion, growth, production of red blood cells, menstrual cycle, and many more processes, which is why clinical manifestations are so varied. Drugs targeting the receptors to modify the signal transduction pathways are being used every day in practice. For example, fenoldopam is a D1 (GsPCR) agonist used for hypertensive emergencies, tamsulosin is alpha1 (GqPCR) antagonist used for benign prostatic hyperplasia, desmopressin is V2 (GsPCR) agonist is used for bedwetting, epoetin is EPO agonist (JAK/STAT pathway) used for anemia associated with chronic kidney disease, and glucagon (GsPCR) injections to treat hypoglycemia.

Although abnormal production is the most common mechanism of disease, it is not the only one; other mechanisms involve different stages of the signaling process; as we saw before, the signaling process entails production, secretion, and reception of the messenger; disruption of any of these processes lead to alteration in signaling.