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GH can be regulated by various factors. The hypothalamus secretes hormones, like the GH releasing factor (GHR) or hormone (GHRH) which can stimulate the pituitary cells and activate different signal transduction cascades. On the other hand, it produces the hormone Somatostatin (SS) which inhibits the GH secretion by blocking the [https://en.wikipedia.org/wiki/Adenylyl_cyclase adenylate cyclase (AC)]. However, not the GH expression. It can also prevent the release of GHRH fom the hypthalamus. In addition, can be inhibited by feedback regulation. It stimulates the steroid and thyroid synthesis which migrate back and inhibit GH. Other regulating factors are environmental influences and the nutritional state. [https://doi.org/10.1016/j.ygcen.2017.07.028 ] | GH can be regulated by various factors. The hypothalamus secretes hormones, like the GH releasing factor (GHR) or hormone (GHRH) which can stimulate the pituitary cells and activate different signal transduction cascades. On the other hand, it produces the hormone Somatostatin (SS) which inhibits the GH secretion by blocking the [https://en.wikipedia.org/wiki/Adenylyl_cyclase adenylate cyclase (AC)]. However, not the GH expression. It can also prevent the release of GHRH fom the hypthalamus. In addition, can be inhibited by feedback regulation. It stimulates the steroid and thyroid synthesis which migrate back and inhibit GH. Other regulating factors are environmental influences and the nutritional state. [https://doi.org/10.1016/j.ygcen.2017.07.028 ] | ||
<StructureSection load='1HGU' size='350' side='right' scene='' caption='Somatotropin : Growth Hormon ([[HGH]])' > | |||
== Structure == | == Structure == | ||
Somatotropin has three major isoforms. The predominant form is composed out of 191 amino acids and has a molecular weight of 22 kDa. | Somatotropin has three major isoforms. The predominant form is composed out of 191 amino acids and has a molecular weight of 22 kDa. | ||
The '''primary structure''', corresponding to a sequence of amino acids, of the predominant somatotropin | The '''primary structure''', corresponding to a [https://www.uniprot.org/uniprot/P01241 sequence of amino acids], of the predominant somatotropin. | ||
Somatotropin does not exist as a linear chain of amino acids, it twists and folds on itself, forming the '''secondary structure'''. The protein, made up of a single chain, consists of four antiparallel aligned <scene name='86/868194/Alpha-helice/2'>α-helices</scene> in an up-up-down-down manner <ref name="Endokrynologika Polska">DOI:10.5603/EP.2013.0009</ref> [https://doi.org/10.1016/j.ghir.2013.02.002]. The first helix starts at the 6th amino acid, which is a leucine and ends with the 37th amino acid proline. It is separated from the other three helices after the 37th position. The 38th and 39th amino acids, which are lysine and glutamic acid are spliced out of the protein and therefore disconnects the first helix from the second one. The second helix starts at position 72 till 92, the third from 106 till 128 and the fourth helix from 154 until 184. All helices are ampipathic with strong <scene name='86/868194/Hydrophobic_regions/1'>hydrophobic regions</scene>, especially helix 2 is very hydrophobic. The [https://en.wikipedia.org/wiki/Hydrophobic_effect#:~:text=Structures%20of%20water%2Dsoluble%20proteins,interact%20with%20surrounding%20water%20molecules. hydrophobic protein core] is usually tigthly packed and any mutations in the hidden positions lead to destablilization <ref name="pubMed">PMID:17584122</ref>. | Somatotropin does not exist as a linear chain of amino acids, it twists and folds on itself, forming the '''secondary structure'''. The protein, made up of a single chain, consists of four antiparallel aligned <scene name='86/868194/Alpha-helice/2'>α-helices</scene> in an up-up-down-down manner <ref name="Endokrynologika Polska">DOI:10.5603/EP.2013.0009</ref> [https://doi.org/10.1016/j.ghir.2013.02.002]. The first helix starts at the 6th amino acid, which is a leucine and ends with the 37th amino acid proline. It is separated from the other three helices after the 37th position. The 38th and 39th amino acids, which are lysine and glutamic acid are spliced out of the protein and therefore disconnects the first helix from the second one. The second helix starts at position 72 till 92, the third from 106 till 128 and the fourth helix from 154 until 184. All helices are ampipathic with strong <scene name='86/868194/Hydrophobic_regions/1'>hydrophobic regions</scene>, especially helix 2 is very hydrophobic. The [https://en.wikipedia.org/wiki/Hydrophobic_effect#:~:text=Structures%20of%20water%2Dsoluble%20proteins,interact%20with%20surrounding%20water%20molecules. hydrophobic protein core] is usually tigthly packed and any mutations in the hidden positions lead to destablilization <ref name="pubMed">PMID:17584122</ref>. | ||
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== HGH receptors and interactions == | == HGH receptors and interactions == | ||
The [https://en.wikipedia.org/wiki/Growth_hormone_receptor#:~:text=8%20External%20links-,Structure,GH%20binding%20protein%20(GHBP). GH membrane receptor (GHR)] is found on many cells and tissues with the exception of the brain, testicles and thymus. It is part of the [[https://en.wikipedia.org/wiki/Type_I_cytokine_receptor class I cytokine receptor family] [https://doi.org/10.1016/j.ygcen.2017.07.028 ]. The nature of this receptor is not fully understood, but it seems that it may be present in different forms due to different post-translational changes that may occur in a single protein.<ref name="m/s"> Le Cam, A. (1993), Mode d’action de l’hormone de croissance. médecine/sciences, 12:1352-61.[http://www.ipubli.inserm.fr/bitstream/handle/10608/2863/MS_1993_12_1352.pdf?sequence=1]</ref> | The [https://en.wikipedia.org/wiki/Growth_hormone_receptor#:~:text=8%20External%20links-,Structure,GH%20binding%20protein%20(GHBP). GH membrane receptor (GHR)] is found on many cells and tissues with the exception of the brain, testicles and thymus. It is part of the [[https://en.wikipedia.org/wiki/Type_I_cytokine_receptor class I cytokine receptor family] [https://doi.org/10.1016/j.ygcen.2017.07.028 ]. The nature of this receptor is not fully understood, but it seems that it may be present in different forms due to different post-translational changes that may occur in a single protein.<ref name="m/s"> Le Cam, A. (1993), Mode d’action de l’hormone de croissance. médecine/sciences, 12:1352-61.[http://www.ipubli.inserm.fr/bitstream/handle/10608/2863/MS_1993_12_1352.pdf?sequence=1]</ref> | ||
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The hormone-binding extracellular domain consists of 250 amino acids, including several cysteine residues which are conserved and can form disulphide bridges.The intracellular domain of the receptor is made up of 350 amino acids, it represents the least conserved region and is made up of 10 tyrosine residues likely to be phosphorylated by tyrosine kinase ([https://en.wikipedia.org/wiki/Janus_kinase_2 JAK2]), during the formation of the GH-receptor complex. A reaction cascade involving kinase enzymes is then activated, allowing the expression of certain genes coding for proteins or not, necessary for biological activity [https://doi.org/10.1016/j.ygcen.2017.07.028 ]. It therefore controls the expression of certain genes such as the gene coding for the IGF-1 factor. The liver and adipose tissue being important targets for GH, it therefore contributes to [https://en.wikipedia.org/wiki/Homeostasis#:~:text=The%20neuroendocrine%20system%20is%20the,hypothalamic%20interconnections%20to%20other%20glands. metabolic homeostasis].<ref name="m/s"/> [https://doi.org/10.1016/j.ygcen.2017.07.028 ] The intercellular domain containing of two box regions. The proline rich first one and an acidic, hydrophobic second one which is connected to receptor internalizing mechanisms [https://doi.org/10.1016/j.ygcen.2017.07.028 ]. | The hormone-binding extracellular domain consists of 250 amino acids, including several cysteine residues which are conserved and can form disulphide bridges.The intracellular domain of the receptor is made up of 350 amino acids, it represents the least conserved region and is made up of 10 tyrosine residues likely to be phosphorylated by tyrosine kinase ([https://en.wikipedia.org/wiki/Janus_kinase_2 JAK2]), during the formation of the GH-receptor complex. A reaction cascade involving kinase enzymes is then activated, allowing the expression of certain genes coding for proteins or not, necessary for biological activity [https://doi.org/10.1016/j.ygcen.2017.07.028 ]. It therefore controls the expression of certain genes such as the gene coding for the IGF-1 factor. The liver and adipose tissue being important targets for GH, it therefore contributes to [https://en.wikipedia.org/wiki/Homeostasis#:~:text=The%20neuroendocrine%20system%20is%20the,hypothalamic%20interconnections%20to%20other%20glands. metabolic homeostasis].<ref name="m/s"/> [https://doi.org/10.1016/j.ygcen.2017.07.028 ] The intercellular domain containing of two box regions. The proline rich first one and an acidic, hydrophobic second one which is connected to receptor internalizing mechanisms [https://doi.org/10.1016/j.ygcen.2017.07.028 ]. | ||
== | </StructureSection> | ||
== Disease == | |||
Many diseases can be due to a dysfunction in the secretion of GH. | Many diseases can be due to a dysfunction in the secretion of GH. | ||
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[https://en.wikipedia.org/wiki/Gigantism '''Gigantism'''] is characterised by the presence of a high level of GH or IGF-1. This pathology is most often due to an [https://en.wikipedia.org/wiki/Adenoma adenoma] of the pituitary cells, responsible for the production of the hormone [https://en.wikipedia.org/wiki/Growth_hormone%E2%80%93releasing_hormone GHRH], which then stimulates the cells to produce GH in large quantities. It can also be explained by the fact that tissues that do not normally produce GH have tumour cells capable of producing GH. [https://en.wikipedia.org/wiki/Acromegaly '''Acromegaly'''] is when this excess of hormone occurs after puberty.<ref name="bgh"/> | [https://en.wikipedia.org/wiki/Gigantism '''Gigantism'''] is characterised by the presence of a high level of GH or IGF-1. This pathology is most often due to an [https://en.wikipedia.org/wiki/Adenoma adenoma] of the pituitary cells, responsible for the production of the hormone [https://en.wikipedia.org/wiki/Growth_hormone%E2%80%93releasing_hormone GHRH], which then stimulates the cells to produce GH in large quantities. It can also be explained by the fact that tissues that do not normally produce GH have tumour cells capable of producing GH. [https://en.wikipedia.org/wiki/Acromegaly '''Acromegaly'''] is when this excess of hormone occurs after puberty.<ref name="bgh"/> | ||
Until 1985, injections of GH were carried out for people suffering from dwarfism. As it could only be obtained by extraction from the pituitary glands of dead people, it could only be extracted in small quantities, so resources were limited. | Until 1985, injections of GH were carried out for people suffering from dwarfism. As it could only be obtained by extraction from the pituitary glands of dead people, it could only be extracted in small quantities, so resources were limited. Also this therapeutic treatment has been stopped in many countries, due to the possible contamination of the hormone by [https://en.wikipedia.org/wiki/Prion prions], which can cause serious diseases such as [https://en.wikipedia.org/wiki/Creutzfeldt%E2%80%93Jakob_disease Creutzfeldt-Jakob disease].<ref name="bgh" /> As a result, biosynthetic synthesis of the hormone is carried out by developing [https://en.wikipedia.org/wiki/List_of_recombinant_proteins recombinant proteins] of GH or IGF-1.<ref name="univ"/> | ||
Affected by gigantism pathology, individuals may have therapeutic radiation and therapeutic drug treatment or synthesis of inhibitors such as [https://en.wikipedia.org/wiki/Somatostatin somatostatin], | Affected by gigantism pathology, individuals may have therapeutic radiation and therapeutic drug treatment or synthesis of inhibitors such as [https://en.wikipedia.org/wiki/Somatostatin somatostatin], which act as GH antagonists by binding to the receptor, thus preventing the GH to perform its functions.<ref name="bgh"/> | ||
== References == | == References == | ||
<references/> | <references/> | ||
