second messengers

Second messengers are small, readily diffusible molecules that operate in signal transduction. (animation 2nd messenger)

calcium ions : cAMP : cGMP : ceramide : diacylglycerol : inositol-1,4,5-trisphosphate (IP3)

Second messengers relay and amplify signals received by cell-surface receptors, and are typically generated by ligand-receptor bonding:
a) produced, degraded by specific enzymatic action
b) some are stored in vesicles
c) production, release, degradation can be localized – A-kinase anchoring proteins (AKAPs) are signal-organizing molecules that compartmentalize the cAMP dependent protein kinase, phosphodiesterases, and a variety of enzymes that are regulated by second messengers'[s].

Second messengers fall into three classes:
1. hydrophobic molecules: membrane-associated diacylglycerol (PKC), InsP3 (PKC), phosphatidylinositols produced from membranous phosphatidylinositol (PtdIns, PI)
2. hydrophilic, cytosolic molecules: cyclic nucleotides cAMP and cGMP, Ca2+ ions
3. gases: NO, CO

cAMP: Hormones such as adrenaline, glucagon, luteinizing hormone (LH), parathyroid hormone (PTH), and adrenocorticotropic hormone (ACTH) cause an increase in the cyclic nucleotide, second messenger cAMP, which is synthesized from ATP by (adenylyl) adenylate cyclases. Activation of adenylyl cylases follows binding to GPCRs, the associated G-proteins of these receptors bind GDP when inactive, and switch the bound nucleotide to GTP when activated. The cyclic-AMP concentration in a cell can produce a variety of pleiotropic effects because the cAMP second messenger controls protein kinases that affect a variety of proteins. At least 20 G-alpha proteins have been identified in mammalian cells.

(GPCR families: B Secretin like: Corticotropin releasing factor, Gonadotropin-releasing hormone, Parathyroid hormone) : animation G-protein :

cGMP: The second messenger, cyclic nucleotide, cGMP is synthesis by guanyl cyclase in response to:
1) photic response of retinal rods
2) Nitric Oxide (NO)
3) atrial natriuretic peptide (ANP), a 28-aa peptide that is released from stretched atria (heart chambers) when blood pressure is elevated

(Class A Rhodopsin like GPCR family: Rhodopsin like: Amine, Peptide, Hormone protein, (Rhod)opsin)

Some second messenger effects of cGMP are mediated via protein kinase G (PKG), which is a cGMP-dependent protein kinase that phosphorylates target proteins in the cell.

Ligands such as the neurotransmitter GABA, and the peptide/protein hormones vasopressin, thyroid-stimulating hormone (TSH), and angiotensin, via GPCRs activate Phospholipase C (PLC), which hydrolyzes membranous phospolipids (phosphatidylinositol-4,5-bisphosphate (PIP2) to yield DAG and IP3, with release of Ca2+.

(Class A Rhodopsin like: Thyrotropin-releasing hormone & Secretagogue, Class B Secretin like: Diuretic hormone, Class C Metabotropic: GABA-B)

Diacylglycerol (DAG) is an intracellular messenger that remains attached to the inner membrane. DAG accumulates transiently in cells exposed to growth factors or other stimuli. Cellular responses such as growth and differentiation are impacted by the binding of DAG to PKC, the action of which requires calcium ions generated by inositol-1,4,5-trisphosphate (IP3, InsP3). Diacylglycerol kinases (DGKs) are responsible for eliminating the function of diacylglycerol (DAG) and for producing phosphatidic acid (PA) (both molecules are connected to cancer).

Inositol-1,4,5-trisphosphate (IP3) diffuses to the endoplasmic reticulum, where it triggers release of Ca2+ ions into the cytosol. Subsequently, the released Ca2+ and DAG activate protein kinase C (PKC).

Ca2+ ions are the most widely employed second messengers:
1. trigger muscle contraction by binding to troponin (after release from sacroplasmic reticulum), which activates actin-myosin interaction,
2. neurotransmitter release at neuronal synapses, where they are essential for long-term potentiation (LTP) and long-term depression (LTD)
3. secretion of hormones (e.g. insulin)
4. apoptosis
5. cell adhesion to extracellular matrix
6. activation of T and B cells of the immune system – calcium ions are necessary for the gene expression that generates NF-AT ("nuclear factor of activated T cells"), an action that is blocked by FK506 and cyclosporine.

Ca2+ release into the cytosol is amplituded and frequency modulated, and is regulated by:
a) voltage-gated channels – after depolarization by an action potential Ca2+ ions are released from storage in the endoplasmic reticulum of smooth-muscle cells, the sarcoplasmic reticulum of striated (voluntary) muscles, taste-receptors for salt, neurons (trigger of nt release)
b) receptor-operated ion channels in post-synaptic membranes, which open upon nt-binding
c) Guanine nucleotide-binding protein-coupled receptors, also termed serpentine receptors (GPCRs), which trigger the release of calcium ions from the endoplasmic reticulum.

Ca2+ is returned to the extracellular fluid by active transport:
a) ATP-driven Ca2+-ATPase pump
b) Na2++/Ca2+antiport exchanger pump that harnesses the energy of 3 Na2++ ions flowing down their concentration gradient to pump one Ca2+ against its concentration gradient
Ca2+ is returned to the endoplasmic/sarcoplasmic reticulum by a Ca2+-ATPase

Ceramide is a well-characterized sphingolipid metabolite and second messenger that participates in numerous biological processes. In addition to serving as a precursor to complex sphingolipids, ceramide is a potent signaling molecule capable of regulating vital cellular functions. Perhaps its major role in signal transduction is to induce cell cycle arrest, and promote apoptosis. In contrast, little is known about the metabolic or signaling pathways that are regulated by the phosphorylated form of ceramide. It was first demonstrated that ceramide-1-phosphate (C1P) had mitogenic properties, and more recently it has been described as potent inhibitor of apoptosis and inducer of cell survival. C1P and ceramide are antagonistic molecules that can be interconverted in cells by kinase and phosphatase activities. An appropriate balance between the levels of these two metabolites seems to be crucial for cell and tissue homeostasis. Switching this balance towards accumulation of one or the other may result in metabolic dysfunction, or disease. Therefore, the activity of the enzymes that are involved in C1P and ceramide metabolism must be efficiently coordinated to ensure normal cell functioning. Gomez-Munoz A. Ceramide 1-phosphate/ceramide, a switch between life and death. Biochim Biophys Acta. 2006 May 19; [Epub ahead of print]

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