Cellular communication is a complex process involving various biochemical steps with several molecules functioning as messengers between cells, or even, inside a single cell. In multicellular organisms, like humans, cells are crowded together and surrounded by extracellular fluid, in which most cellular messengers travel to reach target cells. To accomplish this, cells use various signaling mechanisms to perform thousands of different functions. Among these, the paracrine signaling is a mechanism in which the sender cell secretes a molecule that acts on a receiver cell in close proximity of the sender cell. In a paracrine pathway, the signaling molecule never enters the bloodstream. In contrast, the endocrine system involves secretion of a molecule by the sender cell followed by the messenger molecule circulating in the bloodstream before acting on a distant receiver cell. Another signaling mechanism is the autocrine mechanism. This pathway functions by the secretion and reception of a messenger molecule by a single cell. Another mechanism of communication is juxtacrine signaling, in which cells communicate by direct contact which each other. All these signals influence the behavior of receiver cells, regulating physiologic processes such as metabolism, transport, motility, division, and growth.
The interaction between a messenger molecule and the target cell is just the beginning of a complex cascade of events that happens intracellularly. Most of the cellular messengers exert their effect through the interaction with a specific receptor coupled to the lipid membrane. There are also intracellular receptors which interact with lipophilic molecules that diffuse through the lipid membrane in both directions, without the help of transport proteins.
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. Examples of cell membrane receptors include G-protein-coupled receptors (GPCR) and receptor tyrosine kinase (RTK). Both of which are well studied with 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 range from subatomic particles, like photons, to ions and finally, complex molecules, like proteins. The ligand binding site of GPCRs are located on extracellular surface membranes, on intracellular surface interacts with heterotrimeric G proteins, those 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 gets classified according to its function as G-alpha-s, G-alpha-i, G-alpha-q, and G-alpha-12. The s type alpha subunit leads to stimulation of enzyme adenylyl cyclase and a consequent increase in cAMP. This second messenger interacts with other effector molecules, making a complex signaling cascade. The i type alpha subunit inhibits adenylyl cyclase and results in cAMP depletion due to the tonic phosphodiesterase activity. The q type alpha subunit activates the phospholipase C; it cleaves phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). These molecules act as second messengers, the release of calcium by endoplasmic reticulum is due to IP3; DAG activates protein kinase C, which causes phosphorylation of many proteins.
The RTK are usually single transmembrane polypeptide chains with an intracellular tyrosine kinase domain, RTKs are involved widely in embryonic development and other important roles in adult life. Examples of RTKs are insulin receptor, vascular endothelial growth factor receptor, nerve growth factor receptor, and fibroblast growth factor receptor.
Embryonic development is a complex process requiring billions of cells to function in unison in an effort 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 messenger molecules are secreted glycoproteins that interact with specific types of GPCRs: the frizzled receptors.
The mechanism by which cellular messengers transmit a signal entails secretion of messengers by a sender cell, distribution in different tissues, and finally, interaction with specific cell surface receptor on the target cell. Different messengers have different signaling ranges; this is the distance between the source of messengers and where a response to them gets elicited. According to distances that messengers travel to generate a response and transmit the signal, we can classify them as described in the following paragraphs.
Long-range signaling: after a sender cell secretes a messenger molecule, this one travel into the bloodstream a long distance throughout the body, to reach the specific receptor on the membrane of the receiver cell. This is called endocrine signaling, hormones of the endocrine system are the best example of long-range signaling, for example, epinephrine, secreted by the adrenal medulla, once in the bloodstream, it can interact with many receptors (adrenoceptors), distributed in several tissues, including the heart, blood vessels, lungs, liver, and kidneys. Adrenoceptors belong to 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, with the objective to stimulate erythroid progenitor cells in the bone marrow to produce more erythrocytes, a process called erythropoiesis.
Short-range signaling: there are two types, the first occurs when a cell secrete a molecule that elicits a response on a neighbor cell, this is called paracrine signaling. The main feature in this process is that messenger molecule travels a short distance to transmit the signal on a nearby cell; therefore, the messenger acts locally, a useful example of paracrine signaling is synapse, in which a presynaptic neuron releases a neurotransmitter into the synaptic cleft and immediately interacts with a postsynaptic neuron. The second type, autocrine signaling, occurs when a sender cell secretes a molecule into extracellular space, but this molecule interacts with a receptor on the surface of the same cell that secretes it. Thus, the sender cell is also the receiver cell.
Ultra short-range signaling: this is a particular type of cellular signaling in which the messenger attaches to the cell membrane of sender cell; therefore, receiver cell needs to be extremely close and have the specific receptor to the messenger; receptors and ligands are both anchored to the membrane. This type of signaling is commonly seen in cells of the immune system and neutrophils when they do extravasation.
Disruption of signaling between cells can lead to disease, an example of this is Graves disease, an autoimmune disease, in which the immune system makes antibodies (autoantibodies) against the thyroid-stimulating hormone receptors located on the surface of thyroid cells. Under physiological circumstances, their activation by the thyroid-stimulating hormone (TSH), leads to production and secretion of thyroid hormones: triiodothyronine (T3) and thyroxine (T4). In Graves disease, autoantibody binds to and activate TSH receptor, leading to an increase in T3 and T4 production, an excess of these hormones produce classical clinical signs, including tachycardia, diffuse goiter, hyperreflexia, fine resting tremor, exophthalmos, and pretibial myxedema. This is but an example of what may occur with disruption of cell communication or signaling; this usually leads to pathologic states.
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 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 much more processes, which is the reason why clinical manifestations are so varied.
Although abnormal production is the most common mechanism of disease, is not the only one, there exist other mechanisms that involve different stages of the signaling process, as we saw before, signaling process entails production, secretion, and reception of the messenger; disruption of any of these processes lead to alteration in signaling.
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