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Living organisms harmonize their activities through pathways mediated by chemical messengers known as hormones. Hormones presence in cells is to either switch on or off certain functions within the cell for the betterment of the cell. ATP is the major fuel utilized in operating molecular switches. These switches must be rapid, reversible and efficient. Most molecular switches can be phsophorylated proteins, mainly on serine and thronine residue and sometimes on the tyrosine residues. This phosphorytaion causes conformational changes to reduce activity, and induce cooperative binding of another protein to interact with it. It is also possible for lipids to be phosphorylated such as inositol lipids. In this essay, the pathways of molecular mechanisms in hormone signalling will be looked at such as G-protein base signalling, tyrosin kinase-base signalling, and the phsophorinositide cascade, the steroid mechanism, and the nuclear factor for kB and cAMP system.
What are hormones?
Hormones are the chemical messengers of the endocrine system that regulates all aspects of metabolism. These hormones are release in the bloodstream in response to stimuli. They are transported to their target cells where they elicit a response as shown in fig1 below.
Hormones signalling are arbitrated via chemical messengers termed hormones, and in higher animals, by neurone transmitted electrochemical impulses. Intracellular communications are maintained through a series of processes of synthesis or alteration of a great multiplicity of different substances fundamental components of the processes they control. Metabolic pathways are an example of regulatory feedback control of allosteric enzymes that metabolites pathways or by the covalent modification of the enzymes. Generally, every signalling pathway comprises of a receptor protein that is specific to the binding hormones or other ligand, a cooperative ligand-binding events to the cell interior, and a series of intracellular responses that may involve the synthesis of a second messenger and or chemical changes catalyzed by kinase and phosphortase. These pathways are coordinated by the succession of events depends on the previous one magnifies the signal.
There are three major pathways of the intracellular signal conversions to intracellular signalling. One involves receptor tyrosine kinases, two utilize heterotrimeric G proteins and three employ phosphoinositide cascades. Hormones function in many ways such as maintain homeostasis, response to wide range of stimuli and followed various cyclic and developmental programs. Most hormones are polypeptides, amino acid derivatives, or steroids. Hormones response in cells is specific to the cell receptors. Only specific cell receptors will response to stimuli under the release of hormones. This therefore makes hormonally messengers quite specific.
Mechanisms of hormone action
Hormones characteristically start their actions within target cells by binding to a receptor. Water soluble hormones (e.g. Polypeptides, proteins and epinephrine) bind to receptor molecules on their outer surface of the plasma membrane. This binding process induces a phorphorylation cascade either directly (e.g. insulin) or indirectly (using second messenger molecules (e.g. glucagon). This result in specific enzyme, and or membrane transport mechanisms being altered. Well researched second messengers including cyclic AMP (cAMP), cyclic GMP (cGMP), the phosphatidynositol-4-5, bisphosphate derivatives diacylglycerol (DAG) and inositol triphosphate (IP3), and calcium ions are an ideal example. Lipid-soluble hormones such as steroid and thyroid hormones have dissimilarity binding method to their specific receptors. These lipid-soluble hormones penetrate their mark cells and attach to specific receptor molecules. Each hormone-receptor complex then attaches to specific regions of the target cell's DNA. This binding mechanism modifies gene expression and causes alteration in the protein profile of the cell.
The second messenger
The binding of hormone molecules to the plasma membrane receptor generates an intracellular signalling known as second messenger. The role of the second messenger is to deliver the hormonal message. This process known as signal transduction also amplifies the original signal. In a simplistic detail, the initiation of a few hormone molecules leads to the production of some multi-secondary messenger molecules such as: cAMP, cGMP, DAG, IP3 and Ca2+. The hormone response interaction resulted from adenylate cyclase, produce cAMP from ATP. This reaction flanked by the receptor and adenylate cyclase, is indicated by a G protein as shown in fig 2 below.
The Adenylate Cyclise Second Messenger system that Controls Glycogenolysis. In the state of an unoccupied receptor, the Gs protein αs subunit bounded GDP and is intricated with the β,γ-dimer. The binding of hormone (1) stimulates the receptor and results to the replacement of GDP with GTP (2). The simulated subunit interacts with and activates adenylate cyclase. (3) The cAMP created attaches to cAMP-dependent protein kinase. Signal transduction terminates once the ligand leaves the receptor, and bound GTP is hydrolyzed to GDP by the GTPase activity within the αs subunit dissociates from adenylate cyclase. Cyclic AMP is deactivated by hydrolysis of AMP, a reaction catalyzed by phosphodiesterase. (4) The αs subunit then reassociates with the β,γ-dimer.
G protein and adeylate cyclase are all membrane-associated proteins. G proteins are named so due to their binding on guanine nucleotides. The G protein that stimulates cAMP synthesis when hormones like glucagon, TSH (thyroid-stimulating hormone), and epinephrine binds, is referred to Gs. G1 inhibits adenylate cyclase and diminish cAMP levels. G proteins bind GDP (guanine-5'-diphosphate) in their unstimulated form. The effect of hormone binding and the consequential conformational change induce receptor to interact with in close proximity Gs protein. The binding of which is then replaced by GTP (guanosine-5'-triphosphate). The activated G protein then interacts with, and stimulates adenylate cyclase.
G proteins predominantly comprises of three subunits: α, β and γ (alpha, beta and gamma). The αs subunit binds guanine nucleotides has GTPase activity, and activates adenylate cyclase when disconnected from the βγ-dimer. Adenylate cyclase forms cAMP molecules, which diffuses into the cytoplasm to bind to and turn on cAMP-dependent protein kinase. This leads the phosphorylation of active protein kinase, and thus, alters the catalytic motion of key authoritarian enzymes.
Adenylate cyclase stays active only as long as it interacts with αs-GTP. As soon as GTP hydrolyzes to GDP, αs, GDP dissociates from adenylate cyclase and reconnects with βΥ-dimer. The cAMP is rapidly hydrolyzed by phosphoiesterase. This is a crucial obligation of second messengers. That is, once generated, the signal must be terminated hastily. cAMP affects target proteins depending on the type of cell. Additionally, numerous hormones may possibly trigger the G protein. Hence, different hormones may elicit the same effect. For instance, glycogen degradation in liver cells is initiated by both epinephrine and glucagon. Adenylate cyclase activity is repressed by some hormones. Such molecules depress cellular protein phosphorylation reactions owing to their receptor interaction with Gi protein. The activation of Gi triggers the dissociation of its α1 subunit from the βΥ-dimer and averts the activation of adenylate cyclase. The classical example is, as its receptors in adipocytes are associated with Gi, PGE1 (prostaglandin E1) depresses lipolysis . Although cGAM is synthesized in nearly all animal cells, its role in cellular metabolism is yet to be defined. However, the synthesis of cGMP from GTP by guanylate cyclase is known. There are two types of guanylate cyclase concerned in signal transduction. Type 1 is membrane bounded, whose extracellular domain of the enzyme is a hormone receptor, while type two is a cytoplasmic enzyme. There are two known types of molecules that activate membrane-bound guanylate cyclase: atrial natriuretic peptide and bacterial enterotoxin. Atrial natriuretic factor (ANF) is a peptide released from heart atrial cells in response to increase blood volume. ANF is biological vasodilatation and diuresis, which appears to be phosphorylating enzyme protein kinase G, is done by cGMP. While, the role of this enzyme in mediating ANF effects is still not clear. ANF activates guanylate cyclise in many types of cells. In the kidney's collecting tubules, ANF-stimulated cGMP synthesis increases renal concentration of Na+ and water. The binding of enterotoxin to another type of guanylate cyclase fond in the plasma membrane of intestinal cells cause diarrhoea. An e.g. of this is the travellers' diarrhoea, which is caused by a strain of E. Coil that produces heat stable entrotoxin. The binding of this toxin to an enterocyte plasma membrane receptor linked to guanylate cyclase triggers extreme discharge of electrolytes and water into the lumen of the small intestine.
The cytoplasmic guanylate cyclase has a heme prosthetic group. This enzyme gets cytoplasmic Ca2+, and therefore, any rise in cytoplasmic Ca2+effects cGMP synthesis. The guanylate cyclase activity is activated by NO (nitrogen oxide). Some data proposes that binding NO to the heme group stimulate the enzyme. In many cell types, (e.g. smooth muscle cells), cGMP activates the execution of ion channels.
The phosphatidylinositol cycle and calcium
The actions of hormones and growth factors are mediated by phosphotidylinositol cycle shown on fig 3 below.
Examples include: acetylcholine (e.g. insulin secretion in pancreatic cells), vasopressin, TRH, GRH and epinephrine (α1 receptors). Phospholipase C cleaves phosphatidylinositiol-4, 5-bisphosphate (PP2) to form the second messenger DAG (diacylglycerol) and IP3 (inositol-1,4,5-triposphate). Phospholipase C is set off by a cascade of hormone induced G protein establishment. Many types of G proteins may be implicated in the phospholipase cycle. GQ shown in fig 3 above specifies the actions of vasopressin.
The protein kinase C is activated by the DAG product of the phospholipase C-catalyzed reaction. The activities of many protein kinase C have been acknowledged. Activated protein kinase C phosphorylates specific regulatory enzymes, depending on the cell, and thereby either activates or deactivates them. Once this is created, IP3 (a calcium receptor channel) diffuses to the calcisome (SER), and binds to a receptor. This causes a rise in the cytoplasmic calcium level, as calcium ions flows via the activated open channel. Recent confirmation indicates that the IP3-stimulated calcium signal is potentiated briefly by the discharge of another signal that activates the plasma membrane calcium channel. Calcium ions are involved in regulation of quite a lot of cellular processes including the activation of plasma membrane-associated protein kinase C. Due to the low levels of calcium even at activated state (approximately 10-16M), its binding sites on regulated proteins must have high affinity for the ion. Many Calcium-binding proteins transform the activity of other proteins in the presence of calcium. Calmodulin is an example of the calcium-binding proteins which arbitrates many calcium- regulated reactions. Indeed, calmodulin is a regulatory subunit for some enzymes (e.g. phosphorylase kinase, which converts phosphorylase b to a in glycogen metabolism).
Steroid and thyroid Hormone mechanism
The effects of signal transduction mechanisms of hydrophobic hormone molecules such as the steroid and thyroid hormones result in change in gene expression. Each type of hormone molecules action induces change in patter of proteins produced by that affected cell. Steroid and thyroid are lipid- soluble hormones that are elated in the blood to the target cells bound to several types of proteins. Some e.g. of steroid transport proteins are: transcortin (known as corticosteroid -binding globulin), androgen-binding protein, sex hormone-bind protein, and albumin. Thyroid hormones are also transported by thyroid-binding globulin and prealbumin. As soon as they arrive at their mark cells, hydrophobic hormone molecule dissociates from their transporters and diffuses throughout the plasma membrane and binds their intracellular receptors. Fig 4 below is the depiction of is process.
The transportation of steroid hormones in the blood is aided via plasma proteins. As soon as they attain a cell and are discharged (1), the hormone molecules diffuse via plasma membrane to bind receptor molecules in cytoplasm (2) or nucleus (3). After activation (4), a cytoplamic hormone-receptor intricate drifts to the nucleus (5). The binding of a stimulated hormone-receptor intricate to HRE series within DNA (6) marks in a modification in the pace of transcription of specific genes, and hence, in the pattern of proteins (7) that the cell produces. The consequence of the steroid hormone is a transformation in the metabolic implementation of the cell.
These receptors have high affinity ligands binding molecules that belong in the large family of structurally similar DNA-binding proteins. The original binding to receptors various occurs in the cytoplasm, (e.g. glucocorticoid), or nucleus (e.g. estrogens, androgens, and thyroid hormone), depending on the nature of hormone complex. Without the present of hormones, many types of receptors have been observed to form complex with other proteins. For instance, unoccupied glucocorticoid receptors found in cytoplasm bound to hsp90 (heat shock protein). This binding of hsp90 to the glucocorticoid receptor avoid the erroneous binding of corticosterone to the receptor induces conformational change of the receptor, which make it dissociation from hsp90. The two hormone-bound receptors links forming a functional complex that then moves into the nucleus. Inside the nucleus, individual hormone-receptors intricate binds to unambiguous DNA segments known as hormone response elements (HRE). This binding of the hormone-receptor intricate to the base sequence of the HRE through zinc finger domains in the receptor could boost or reduces the transcription of the precise gene. Numerous HREs can attack to the same hormone-receptor complex so the phrase of several genes is transformed concurrently. The ballpark influence of each type of HRE on transcription is up to 50-100 genes. Consequently, this binding effect of steroid hormone-receptor complex to its associated HRE brings a huge transformation in cellular function.
Once thyroid hormones penetrate a cell, it temporarily attach to a precise cytoplasmic protein. Thyroid hormones molecules then drift to the nucleus and mitochondria, and bind to their receptors. In the nucleus the binding of thyroid hormones instigates the transcription of genes which is pivotal in a range of cellular processes, for instance the coding of growth hormone and Na+/K+ ATPase. Thyroid hormones also encourage oxygen utilization and amplified fatty acid oxidation in mitochondria, although, this mechanism is not yet verified.
The Insulin Receptor
The insulin receptor belong to a family of cell surface receptors of different anabolic polypeptides namely, EGF, PDGF, and IGF-I. While the structurally disparity among this group is very large, they have the following features in common: and outer domain with specific binding extracellular ligands, a transmembrane segment, and a cytoplasmic catalytic domain with tyrosine kinase activity. The phosphorylation cascade that triggers autophosphorylation of the tyrosine kinase domain is set off by the tyrosine kinase activity. The binding effect of ligand to the external domain brings about the conformational change in the receptor protein stimulates the tyrosine kinase domain. The insulin receptor fig 5 below is a transmembrane glycoprotein composed of two types of subunits linked by disulfide bridges.
The alpha (α) subunits is the larger subunits (130KD); expand extracellularly forming insulin binding sites. The two small beta (β) subunits (90KD) each hold a transmembrane fragment and a tyrosine kinase domain. The binding of insulin stimulates receptor tyrosine kinase activity and triggers phosphorylation cascade that transforms different intracellular proteins. For instant, the hormone-sensitive lipase in adipocytes is inhibited by the binding of insulin. This inhibition apparently happens as a result of the activation of phosphatase that dephosphorylates the lipase. Additionally, a numerous representations of insulin actions propose that several second messengers are engaged, for example, protein kinase C is activated by inositol monophosphate or DAG. The binding effects of insulin materialize the instigation phosphorylation cascade that triggers the relocation of several types of protein to the cell surface. The isoforms of the glucose transporter and the receptors for LDL (low density lipoprotein) and IGF-ll are examples. The faction of these molecules to the plasma membrane in the postaborptive stage of the feeding-fast cycle supports the cell's attainment of nutrients and growth-promoting signals.
The molecular mechanism of hormone signalling is propagated by receptor proteins that specifically binds a hormone or other ligand, thereby causing transduction in the cell interior through a series of intracellular responses that involved the synthesis of a second messenger and/or chemical transformation catalyzed by kinases and phosphatises.