Cerebral Signal Transduction: From First to Fourth Messengers

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The many types of neuronal nicotinic AChRs are located at synapses between neurons, such as in the CNS where they are involved in cognitive function, learning and memory, arousal, reward, motor control and analgesia. The binding of acetylcholine to nicotinic AChRs brings about their activation.

Cerebral Signal Transduction - From First to Fourth Messengers | Maarten Reith | Springer

When two molecules of acetylcholine bind a nicotinic AchR, a conformational change occurs in the receptor, resulting in the formation of an ion pore. At the neuromuscular junction, the opening of a pore produces a rapid increase in the cellular permeability of sodium and calcium ions, resulting in the depolarisation and excitation of the muscle cell, thereby producing a muscular contraction. The activation of neuronal nicotinic AChRs also causes the movement of cations through the opening of an ion channel, with the influx of calcium ions affecting the release of neurotransmitters.

Nicotinic AChRs on a postganglionic neuron are responsible for the initial fast depolarisation of that neuron. However, the subsequent hyperpolarisation and slow depolarisation, which represent the recovery of the postganglionic neuron from stimulation, are mediated by muscarinic AChR types M2 and M1, respectively.

These subunits are found in different combinations in different types of nicotinic AChRs:. Theses receptors span the membrane, containing extracellular, transmembrane and cytoplasmic domains, the latter being the most variable. Nicotinic receptors are always pentamers, with the subunits arranged symmetrically around a central receptor channel.


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The receptors always contain two or more alpha subunits, which are critical in acetylcholine binding. The acetylcholine-binding site is comprised of a dimer formed by the alpha subunits principal component plus an adjacent subunit complementary component , where binding to both sites is required for the channel to open. Neurotoxins frequently target the acetylcholine-binding site, reversibly blocking the opening of the ion channel and formation of a pore, thereby preventing cations from passing through.

Once activated, these exchange factors can activate more small G proteins, thus amplifying the receptor's initial signal. The mutation of certain RTK genes, as with that of GPCRs, can result in the expression of receptors that exist in a constitutively activated state; such mutated genes may act as oncogenes. Histidine-specific protein kinases are structurally distinct from other protein kinases and are found in prokaryotes, fungi, and plants as part of a two-component signal transduction mechanism: a phosphate group from ATP is first added to a histidine residue within the kinase, then transferred to an aspartate residue on a receiver domain on a different protein or the kinase itself, thus activating the aspartate residue.

Integrins are produced by a wide variety of cells; they play a role in cell attachment to other cells and the extracellular matrix and in the transduction of signals from extracellular matrix components such as fibronectin and collagen. Ligand binding to the extracellular domain of integrins changes the protein's conformation, clustering it at the cell membrane to initiate signal transduction.

Role of G-Proteins in Signal Transduction

Integrins lack kinase activity; hence, integrin-mediated signal transduction is achieved through a variety of intracellular protein kinases and adaptor molecules, the main coordinator being integrin-linked kinase. Important differences exist between integrin-signaling in circulating blood cells and non-circulating cells such as epithelial cells ; integrins of circulating cells are normally inactive. For example, cell membrane integrins on circulating leukocytes are maintained in an inactive state to avoid epithelial cell attachment; they are activated only in response to stimuli such as those received at the site of an inflammatory response.

In a similar manner, integrins at the cell membrane of circulating platelets are normally kept inactive to avoid thrombosis. Epithelial cells which are non-circulating normally have active integrins at their cell membrane, helping maintain their stable adhesion to underlying stromal cells that provide signals to maintain normal functioning.


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    Overview of cell signaling

    When activated, toll-like receptors TLRs take adapter molecules within the cytoplasm of cells in order to propagate a signal. Thousands of genes are activated by TLR signaling, implying that this method constitutes an important gateway for gene modulation. A ligand-gated ion channel, upon binding with a ligand, changes conformation to open a channel in the cell membrane through which ions relaying signals can pass.

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    An example of this mechanism is found in the receiving cell of a neural synapse. The influx of ions that occurs in response to the opening of these channels induces action potentials , such as those that travel along nerves, by depolarizing the membrane of post-synaptic cells, resulting in the opening of voltage-gated ion channels.

    This results in amplification of the synapse response between synaptic cells by remodelling the dendritic spines involved in the synapse. Intracellular receptors, such as nuclear receptors and cytoplasmic receptors , are soluble proteins localized within their respective areas. The typical ligands for nuclear receptors are non-polar hormones like the steroid hormones testosterone and progesterone and derivatives of vitamins A and D. To initiate signal transduction, the ligand must pass through the plasma membrane by passive diffusion. On binding with the receptor, the ligands pass through the nuclear membrane into the nucleus , altering gene expression.

    Activated nuclear receptors attach to the DNA at receptor-specific hormone-responsive element HRE sequences, located in the promoter region of the genes activated by the hormone-receptor complex. Due to their enabling gene transcription, they are alternatively called inductors of gene expression. All hormones that act by regulation of gene expression have two consequences in their mechanism of action; their effects are produced after a characteristically long period of time and their effects persist for another long period of time, even after their concentration has been reduced to zero, due to a relatively slow turnover of most enzymes and proteins that would either deactivate or terminate ligand binding onto the receptor.

    Nucleic receptors have DNA-binding domains containing zinc fingers and a ligand-binding domain; the zinc fingers stabilize DNA binding by holding its phosphate backbone. DNA sequences that match the receptor are usually hexameric repeats of any kind; the sequences are similar but their orientation and distance differentiate them.

    The ligand-binding domain is additionally responsible for dimerization of nucleic receptors prior to binding and providing structures for transactivation used for communication with the translational apparatus. Steroid receptors are a subclass of nuclear receptors located primarily within the cytosol.

    How cells signal to each other

    In the absence of steroids, they associate in an aporeceptor complex containing chaperone or heatshock proteins HSPs. The HSPs are necessary to activate the receptor by assisting the protein to fold in a way such that the signal sequence enabling its passage into the nucleus is accessible. Steroid receptors, on the other hand, may be repressive on gene expression when their transactivation domain is hidden.

    Receptor activity can be enhanced by phosphorylation of serine residues at their N-terminal as a result of another signal transduction pathway, a process called crosstalk. Retinoic acid receptors are another subset of nuclear receptors. They can be activated by an endocrine-synthesized ligand that entered the cell by diffusion, a ligand synthesised from a precursor like retinol brought to the cell through the bloodstream or a completely intracellularly synthesised ligand like prostaglandin. These receptors are located in the nucleus and are not accompanied by HSPs. They repress their gene by binding to their specific DNA sequence when no ligand binds to them, and vice versa.

    Certain intracellular receptors of the immune system are cytoplasmic receptors; recently identified NOD-like receptors NLRs reside in the cytoplasm of some eukaryotic cells and interact with ligands using a leucine-rich repeat LRR motif similar to TLRs. Second messengers are the substances that enter the cytoplasm and act within the cell to trigger a response. In essence, second messengers serve as chemical relays from the plasma membrane to the cytoplasm, thus carrying out intracellular signal transduction.

    The release of calcium ions from the endoplasmic reticulum into the cytosol results in its binding to signaling proteins that are then activated; it is then sequestered in the smooth endoplasmic reticulum [47] and the mitochondria. The nature of calcium in the cytosol means that it is active for only a very short time, meaning its free state concentration is very low and is mostly bound to organelle molecules like calreticulin when inactive. Calcium is used in many processes including muscle contraction, neurotransmitter release from nerve endings, and cell migration.

    The three main pathways that lead to its activation are GPCR pathways, RTK pathways, and gated ion channels; it regulates proteins either directly or by binding to an enzyme. Lipophilic second messenger molecules are derived from lipids residing in cellular membranes; enzymes stimulated by activated receptors activate the lipids by modifying them.

    Examples include diacylglycerol and ceramide , the former required for the activation of protein kinase C. Nitric oxide NO acts as a second messenger because it is a free radical that can diffuse through the plasma membrane and affect nearby cells. It is synthesised from arginine and oxygen by the NO synthase and works through activation of soluble guanylyl cyclase , which when activated produces another second messenger, cGMP. NO can also act through covalent modification of proteins or their metal co-factors; some have a redox mechanism and are reversible. It is toxic in high concentrations and causes damage during stroke , but is the cause of many other functions like relaxation of blood vessels, apoptosis , and penile erections.

    In addition to nitric oxide, other electronically activated species are also signal-transducing agents in a process called redox signaling. Examples include superoxide , hydrogen peroxide , carbon monoxide , and hydrogen sulfide. Redox signaling also includes active modulation of electronic flows in semiconductive biological macromolecules. Gene activations [49] and metabolism alterations [50] are examples of cellular responses to extracellular stimulation that require signal transduction.

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    Gene activation leads to further cellular effects, since the products of responding genes include instigators of activation; transcription factors produced as a result of a signal transduction cascade can activate even more genes. Hence, an initial stimulus can trigger the expression of a large number of genes, leading to physiological events like the increased uptake of glucose from the blood stream [50] and the migration of neutrophils to sites of infection. The set of genes and their activation order to certain stimuli is referred to as a genetic program.

    Mammalian cells require stimulation for cell division and survival; in the absence of growth factor , apoptosis ensues. Such requirements for extracellular stimulation are necessary for controlling cell behavior in unicellular and multicellular organisms; signal transduction pathways are perceived to be so central to biological processes that a large number of diseases are attributed to their disregulation.

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    Three basic signals determine cellular growth:. The combination of these signals are integrated in an altered cytoplasmic machinery which leads to altered cell behaviour. Following are some major signaling pathways, demonstrating how ligands binding to their receptors can affect second messengers and eventually result in altered cellular responses.

    The earliest notion of signal transduction can be traced back to , when Claude Bernard proposed that ductless glands such as the spleen , the thyroid and adrenal glands , were responsible for the release of "internal secretions" with physiological effects. The discovery of nerve growth factor by Rita Levi-Montalcini in , and epidermal growth factor by Stanley Cohen in , led to more detailed insights into the molecular basis of cell signaling, in particular growth factors.

    In , Martin Rodbell examined the effects of glucagon on a rat's liver cell membrane receptor. He noted that guanosine triphosphate disassociated glucagon from this receptor and stimulated the G-protein , which strongly influenced the cell's metabolism. Thus, he deduced that the G-protein is a transducer that accepts glucagon molecules and affects the cell. Thus, the characterization of RTKs and GPCRs led to the formulation of the concept of "signal transduction", a word first used in The term first appeared in a paper's title in From Wikipedia, the free encyclopedia.

    This article is about signaling at the cellular level. For systemic signal transduction, see Transduction physiology.