{"id":833,"date":"2020-02-17T22:10:27","date_gmt":"2020-02-17T16:40:27","guid":{"rendered":"https:\/\/medicineplexus.com\/?p=833"},"modified":"2020-02-17T22:10:27","modified_gmt":"2020-02-17T16:40:27","slug":"second-messenger-systems","status":"publish","type":"post","link":"https:\/\/medicineplexus.com\/second-messenger-systems\/","title":{"rendered":"Second messenger systems"},"content":{"rendered":"\n<p><strong>Second messenger systems<\/strong><\/p>\n\n\n\n<p><strong>Signal Transduction<\/strong><\/p>\n\n\n\n<ul><li>An effective and well-regulated relay or transduction of extracellular signals is crucial for normal cell behavior.<\/li><li>This transduction of extracellular signals happens through an agency of primary as well as secondary messengers.<\/li><li>Aberrant signaling often leads to diverse pathological consequences.<\/li><li>These signalings offer potential targets for drug therapy.<\/li><\/ul>\n\n\n\n<p><strong>Why second messengers are needed?<\/strong><\/p>\n\n\n\n<ul><li>Hydrophilic messengers cannot cross the cell membrane<\/li><li>This restriction forces them to produce intracellular second messengers which are responsible for the effects of the various messengers<\/li><li>Ligand binds to receptors and the resultant ligand-receptor complex is coupled to an enzyme and stimulates the conversion of some metabolite into a second messenger<\/li><li>This second messenger then mediates all the effects of the primary messenger inside the cell in question&nbsp;<\/li><li><strong>Second messengers &#8211; are molecules that relay signals from receptors on the cell surface to target molecules inside the cell, in the cytoplasm or nucleus.<\/strong><\/li><li>Basically, they serve as <strong>relay molecules to primary messengers<\/strong><\/li><li>In addition, they <strong>greatly amplify the strength of the signal<\/strong><\/li><li>Targeting the second messenger signaling represent a new and promising approach to therapeutics including cancers.<\/li><\/ul>\n\n\n\n<p><strong>Types of second messenger molecules<\/strong><\/p>\n\n\n\n<ul><li><strong>Hydrophobic molecules: <\/strong>Diacylglycerol (DAG), and Phosphatidylinositol (PI) \u2013 membrane associated<\/li><li><strong>Hydrophilic molecules: <\/strong>cAMP, cGMP, IP3, and Ca2+ \u00e0 within the cytosol<\/li><li><strong>Gases: <\/strong>Nitric oxide (NO) and Carbon monoxide (CO) \u00e0can diffuse both through cytosol and across cellular membranes.<\/li><\/ul>\n\n\n\n<p><strong>G Proteins &amp; GPCRs<\/strong><\/p>\n\n\n\n<ul><li>Because of their number and physiological importance, GPCRs are the targets for many drugs; perhaps half of all non-antibiotic prescription drugs act at these receptors<\/li><li>When a\u00a0ligand\u00a0activates the\u00a0G protein-coupled receptor, it induces a conformational change in the receptor<\/li><li>allows the receptor to function as a\u00a0guanine nucleotide exchange factor\u00a0(GEF) that exchanges GTP in place of GDP on the G<sub>\u03b1<\/sub>\u00a0subunit in the traditional view of heterotrimeric protein activation.<\/li><li>This exchange triggers the dissociation of the G<sub>\u03b1<\/sub>\u00a0subunit, bound to GTP, from the G<sub>\u03b2\u03b3<\/sub>\u00a0dimer and the receptor.<\/li><li>The G<sub>\u03b1<\/sub>\u00a0subunit will eventually\u00a0hydrolyze\u00a0the attached GTP to GDP by its inherent\u00a0enzymatic\u00a0activity, allowing it to re-associate with G<sub>\u03b2\u03b3<\/sub>\u00a0and starting a new cycle.<\/li><\/ul>\n\n\n\n<p><strong>GPCR mutations in health and disease <\/strong><strong>\u00e0<\/strong><\/p>\n\n\n\n<p><strong>Pseudohypoparathyroidism&#8211; type I (PHP 1)<\/strong><\/p>\n\n\n\n<ul><li>Caused by mutational inactivation of the \u03b1 subunit of Gs<\/li><li>Multiple endocrine abnormalities in cAMP regulated organs<\/li><li>Short stature, Obesity, Round face, One or more foreshortened metacarpal or metatarsal bones, Subcutaneous calcifications<\/li><\/ul>\n\n\n\n<p><strong>McCune Albright syndrome<\/strong><\/p>\n\n\n\n<ul><li>Somatic mutation in \u03b1s in early embryonic development<\/li><li>Patients mosaic&nbsp; for constitutively active Gs (\u03b1s)<\/li><li>Polyostotic fibrous dysplasia, Precocious puberty<\/li><\/ul>\n\n\n\n<p><strong>Disruption of G protein signaling-<\/strong><\/p>\n\n\n\n<ul><li><strong>Cholera toxin &#8211; <\/strong>Modifies Gs so that it cannot be inactivated<\/li><li><strong>Pertussis toxin &#8211; <\/strong>Modifies Gi so that it cannot inhibit adenylyl cyclase<\/li><\/ul>\n\n\n\n<figure class=\"wp-block-image size-large\"><img loading=\"lazy\" decoding=\"async\" width=\"405\" height=\"284\" src=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-342.png?w=405\" alt=\"\" class=\"wp-image-845\" srcset=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-342.png 405w, https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-342-300x210.png 300w\" sizes=\"(max-width: 405px) 100vw, 405px\" \/><\/figure>\n\n\n\n<p><strong>Cyclic GMP and NO signaling pathway<\/strong><\/p>\n\n\n\n<figure class=\"wp-block-image size-large\"><img loading=\"lazy\" decoding=\"async\" width=\"562\" height=\"416\" src=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-343.png?w=562\" alt=\"\" class=\"wp-image-846\" srcset=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-343.png 562w, https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-343-300x222.png 300w\" sizes=\"(max-width: 562px) 100vw, 562px\" \/><\/figure>\n\n\n\n<p><strong>Phosphoinositol pathway<\/strong><\/p>\n\n\n\n<figure class=\"wp-block-image size-large\"><img loading=\"lazy\" decoding=\"async\" width=\"397\" height=\"225\" src=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-344.png?w=397\" alt=\"\" class=\"wp-image-847\" srcset=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-344.png 397w, https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-344-300x170.png 300w\" sizes=\"(max-width: 397px) 100vw, 397px\" \/><\/figure>\n\n\n\n<p><strong>Drugs and Hormones acting through IP3\/DAG pathway<\/strong><\/p>\n\n\n\n<ul><li>\u03b1<sub>1<\/sub> agonist, H<sub> 1 <\/sub>&nbsp;agonist, M<sub> 1 <\/sub>, M<sub>3<\/sub> agonist<\/li><li>5HT<sub>2<\/sub> agonist, AT<sub>1 <\/sub>&nbsp;agonist, Bradykinin, Leukotriene agonist, PAF agonist, Vasopressin<\/li><li>Oxytocin, Thromboxane<\/li><\/ul>\n\n\n\n<p><strong>PROTEIN KINASE C<\/strong><\/p>\n\n\n\n<ul><li>Protein kinase C is a family of ser\/thr protein kinases which include molecules whose activities require stimulation by both DAG and Ca2+, by DAG alone, by Ca2+ alone&nbsp; or do not require 2<sup>nd<\/sup> messenger stimulation<\/li><li><strong>Increased levels of PKC<\/strong> associated with malignant transformation in cell lines including<ul><li><strong>Breast, lung and gastric carcinomas<\/strong><\/li><\/ul><ul><li><strong>Inhibition of PKC may have an impact on the invasive and metastatic potential of malignant cells.<\/strong><strong><\/strong><\/li><\/ul><\/li><\/ul>\n\n\n\n<p><strong>PHOSPHODIESTERASES<\/strong><\/p>\n\n\n\n<ul><li>Cyclic nucleotide phosphodiesterases form another family of important signaling proteins<\/li><li>Activities are regulated via the rate of gene transcription as well as by second messengers and interactions with other signaling proteins such as&nbsp; arrestin and protein kinases.<\/li><li>PDEs hydrolyze the cyclic 3&#8242;,5&#8242;-phosphodiester bond in cAMP and cGMP, thereby terminating their action.<\/li><\/ul>\n\n\n\n<p><strong>Disease targets for isoenzyme selective PDE inhibitors<\/strong><\/p>\n\n\n\n<figure class=\"wp-block-image size-large\"><img loading=\"lazy\" decoding=\"async\" width=\"389\" height=\"230\" src=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-345.png?w=389\" alt=\"\" class=\"wp-image-848\" srcset=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-345.png 389w, https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-345-300x177.png 300w\" sizes=\"(max-width: 389px) 100vw, 389px\" \/><\/figure>\n\n\n\n<p><strong>Ceramide-The lipid second messenger<\/strong><\/p>\n\n\n\n<ul><li>Two major actions of ceramides are<ul><li><em>promotion of cell cycle arrest<\/em><\/li><li><em>induction of apoptosis<\/em>.<\/li><\/ul><\/li><li><em>mediator of inflammatory responses through arachidonic acid and prostaglandin<\/em><\/li><\/ul>\n\n\n\n<p><strong>Ceramide<\/strong> as a second messenger mediates<\/p>\n\n\n\n<ul><li>Apoptosis, cell growth, differentiation, senescence,<ul><li>Diabetes, insulin resistance,<\/li><\/ul><ul><li>Inflammation,<\/li><\/ul><ul><li>Neurodegenerative disorders<\/li><\/ul><ul><li>Atherosclerosis<\/li><\/ul><\/li><li><em>Finding selective inhibitors of the enzymes involved ceramides metabolism as well as agonists and antagonists of these receptors will enhance our knowledge and understanding on how these molecules can control physiological and pathological processes\u201d<\/em><\/li><\/ul>\n\n\n\n<p><strong>Zinc &#8211; intracellular second messenger<\/strong><\/p>\n\n\n\n<ul><li>structural constituent of a great number of proteins, including enzymes of cellular signaling pathways and transcription factors, and it is essential for their biological activity.<\/li><li>source of zinc probably one of the intracellular compartment, possibly the ER.<\/li><\/ul>\n","protected":false},"excerpt":{"rendered":"<p>Second messenger systems Signal Transduction An effective and well-regulated relay or transduction of extracellular signals is crucial for normal cell behavior. This transduction of extracellular signals happens through an agency of primary as well as secondary messengers. Aberrant signaling often leads to diverse pathological consequences. These signalings offer potential targets for drug therapy. Why second[&#8230;]\n","protected":false},"author":3,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_seopress_robots_primary_cat":"","_seopress_titles_title":"","_seopress_titles_desc":"","_seopress_robots_index":"","footnotes":""},"categories":[3],"tags":[],"_links":{"self":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/posts\/833"}],"collection":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/users\/3"}],"replies":[{"embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/comments?post=833"}],"version-history":[{"count":0,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/posts\/833\/revisions"}],"wp:attachment":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/media?parent=833"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/categories?post=833"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/tags?post=833"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}