Signal transduction pathways

DR. MOHAMMAD AAMIR HALEEM
1ST YEAR RESIDENT DEPARTMENT OF PATHOLOGY, PIMS, KARIMANAGAR, TELENAGANA

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3. 1.INTRODUCTION In human body, numerous processes are required for coordinating individual cells to support the body as a whole. At the cellular level, Sensing of environments and cell communication for coordination relies on signal transduction; modeling signal transduction systems as self-organizing allows one to explain how equilibria are maintained. Many disease processes, such as  diabetes  and  heart disease  arise from defects or dysregulations in these pathways, highlighting the importance of these processes in human biology and medicine 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 4

4. Cell communication   occurs through chemical signals and cellular receptors by either the  1) direct contact of molecules on two cells surfaces or the 2) release of a "chemical signal" recognized by another cell (near or far). Hormones are carried by the circulatory systems to many sites. Growth factors are released to act on nearby tissues. Ligands are signals that bind cell surface receptors (as observed with insulin (a ligand) and the insulin receptor) or that can pass into the cell and bind an internal receptor (such as the steroid hormones). 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 5

5. 2. SIGNAL TRANSDUCTION Any process occurring within cells that convert one kind of signal/stimulus into another type . It also known as cell signaling in which the transmission of molecular signals  from a cell's exterior to its interior.  Signals received by cells must be transmitted effectively into the cell to ensure an appropriate response. This step is initiated by cell-surface receptors which triggers a biochemical chain of events inside the cell, creating a response. 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 6

6. It  is also defined as the ability of a cell to change behavior in response to a receptor-ligand interaction.(signal) The ligand is the primary messenger . As the result of binding the receptor, other molecules or second messengers are produced within the target cell.  Second messengers relay the signal from one location to another (such as from plasma membrane to nucleus ) leading to cascade of events/changes within a cell   19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 7

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8. Messenger molecules may be amino acids, peptides, proteins, fatty acids, lipids, nucleosides or nucleotides.  Hydrophilic messengers bind to cell membrane receptors.  Hydrophobic messengers bind to intracellular receptors which regulate expression of specific genes. 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 9

9. A ligand binds its receptor through a number of specific weak non-covalent bonds by fitting into a specific binding site or " pocket ". In situations where even low concentrations of a ligand will result in binding of most of the cognate receptors, the receptor affinity is considered to be high . Low receptor affinity occurs when a high concentration of the ligand is required for most receptors to be occupied.  The dissociation constant ( Kd) is the concentration of ligand required to occupy one half of the total available receptors.  19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 10

10. With prolonged exposure to a ligand (and occupation of the receptor) cells often become desensitized.  Desensitization of the cell to a ligand depends upon receptor down-regulation. Desensitization may lead to tolerance, a phenomenon that results in the loss of medicinal effectiveness of some medicines that are over prescribed.  19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 11

11. 3.RECEPTORS Receptors can be roughly divided into two major classes:  intracellular  receptors and  extracellular  receptors . 4.EXTRACELLULAR RECEPTORS Extracellular receptors are integral transmembrane proteins and make up most receptors. They span the plasma membrane of the cell, with one part of the receptor on the outside of the cell and the other on the inside. Signal transduction occurs as a result of a ligand binding to the outside region of the receptor (the ligand does not pass through the membrane). 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 12

12. Various Extracellular Receptors G protein-coupled receptors. Receptors with Kinase activity. Integrin receptors. Toll gate receptors. Ligand-gated ion channel receptors. 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 13

13. 4a. G PROTEIN–COUPLED RECEPTORS  ( GPCRs ) Also known as  seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, and  G protein–linked receptors (GPLR ). These constitute a large protein family of receptors that sense molecules  outside the cell and activate inside signal transduction pathways and, ultimately, cellular responses . Coupling with G proteins, they are called seven-transmembrane receptors because they pass through the cell membrane seven times. 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 14

14. The  ligands  that bind and activate these receptors include light-sensitive compounds ,  odors , pheromones, hormones, and   neurotransmitters, and vary in size from small molecules to peptides to large proteins. G protein–coupled receptors are involved in many diseases, and are also the target of approximately 40% of all modern medicinal drugs . 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 15

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16. G proteins , also known as  guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. When they are bound to GTP , they are 'on', and, when they are bound to GDP, they are 'off '. G proteins belong to the larger group of enzymes called  GTPases 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 17

17. There are two classes of G proteins. The first function as  monomeric   small GTPases , The second form and function as heterotrimeric G protein complexes. Heterotrimeric class of complexes is made up of   alpha  (α),  beta  (β) and  gamma  (γ)  subunits .   The beta and gamma subunits can form a stable dimeric complex referred to as the  beta-gamma complex while alpha subunit dissociates on activation. 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 18

18. MECHANISM It is known that in the inactive state, the GPCR is bound to a  heterotrimeric G protein complex . Binding of an agonist to the GPCR results in a conformation change in the receptor that is transmitted to the bound G α subunit of the heterotrimeric G protein. The activated G α  subunit exchanges  GTP  in place of  GDP  which in turn triggers the dissociation of G α  subunit from the G βγ  dimer and from the receptor . 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 19

19. CONTD.. The dissociated G α   and G βγ  subunits interact with other intracellular proteins to continue the signal transduction cascade. While the freed GPCR is able to rebind to another heterotrimeric G protein to form a new complex that is ready to initiate another round of signal transduction. 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 20

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21. There are two principal signal transduction pathways involving the G protein–coupled receptors : A. the  cAMP signal pathway and B. the   phosphatidylinositol signal pathway. A. cAMP-DEPENDENT PATHWAY , It is also known as the  adenylyl cyclase  pathway. In a cAMP-dependent pathway , the activated G s  alpha subunit binds to and activates an enzyme called  adenylyl cyclase , which, in turn, catalyzes the conversion of  ATP   into cyclic adenosine monophosphate  (cAMP ).   19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 22

22. 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 23 Increases in concentration of the second messenger cAMP may lead to the activation of: cyclic nucleotide-gated ion channels . exchange proteins activated by cAMP ( EPAC) such as  RAPGEF3 popeye domain containing proteins ( Popdc ) an enzyme called  protein kinase A (PKA ).

23. The PKA enzyme is also known as cAMP-dependent enzyme because it gets activated only if cAMP is present. Once PKA is activated, it phosphorylates a number of other proteins including : enzymes that convert  glycogen  into  glucose enzymes that promote muscle contraction in the heart leading to an increase in heart rate transcription factors , which regulate gene expression 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 24

24. Molecules that activate cAMP pathway include : cholera toxin  - increase cAMP levels caffeine  and  theophylline  inhibit cAMP phosphodiesterase, which degrades cAMP - thus enabling higher levels of cAMP than would otherwise be had. pertussis toxin , which increase cAMP levels by inhibiting Gi to its GDP (inactive) form. This leads to an increase in adenylyl cyclase activity, thereby increasing cAMP levels, which can lead to an increase in insulin and therefore hypoglycemia 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 25

25. DEACTIVATION The G s  alpha subunit slowly catalyzes the hydrolysis of GTP to GDP, which in turn deactivates the G s  protein, shutting off the cAMP pathway. The pathway may also be deactivated downstream by directly inhibiting adenylyl cyclase or dephosphorylating the proteins phosphorylated by PKA. Molecules that inhibit the cAMP pathway include: cAMP phosphodiesterase  dephosphorylates cAMP into AMP, reducing the cAMP levels G i  protein, which is a G protein that inhibits adenylyl cyclase, reducing cAMP levels. 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 26

26. B. PHOSPHATIDYLINOSITOL SIGNAL PATHWAY; In the phosphatidylinositol signal pathway, the extracellular signal molecule binds with the G-protein receptor (G q ) on the cell surface and activates  phospholipase C , which is located on the plasma membrane . 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 27 phospholipase C

27. 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 28 IP3 binds with the  IP3 receptor in the membrane of the smooth endoplasmic reticulum and mitochondria to open Ca 2+  channels. DAG helps activate  protein kinase C (PKC), which phosphorylates many other proteins, changing their catalytic activities, leading to cellular responses.

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29. The effects of Ca 2+   are also remarkable: It cooperates with DAG in activating PKC and can activate the  CaM kinase  pathway, in which calcium-modulated protein  calmodulin (CaM) binds Ca 2+ , undergoes a change in conformation, and activates CaM kinase. The kinase then phosphorylates target enzymes, regulating their activities. The two signal pathways are connected together by Ca 2+ -CaM , which is also a regulatory subunit of adenylyl cyclase and phosphodiesterase in the cAMP signal pathway. 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 30

30. WHEN G PROTEIN SIGNALING IS DISRUPTED G protein-related diseases are characterized by either deficient or excessive G protein signal transmission, which arises through abnormal signal initiation, defective termination, or reduced levels of G proteins Deficient G protein signaling can arise through either reduced levels of G proteins, or through decrease signal initiation. 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 31

31. Diseases involving a decrease in the production of G proteins include; Night Blindness , where mutations in G(t) protein a subunits affect the response of rod cells to light . Pseudo hypoparathyroidism , where the genetic loss of G(s) protein a subunits results in non-responsiveness to parathyroid hormone.  Other abnormalities involve decreased signal initiation through the inability of G proteins to switch to active states, e.g. the symptoms of Whooping Cough ( Pertussis) like hypoglycemia 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 32

32. Excessive G protein signaling can arise through either increased signal initiation , or defective signal termination . Increased signal initiation occurs in Testotoxicosis , where a mutation in the receptor for luteinizing hormone can over-stimulate G(s) proteins, resulting in the excessive production of testosterone . Diseases arising from defective signal termination result from the persistent elevated activity of downstream effectors, such as in Cholera , the symptoms of which results from the action of a bacterial toxin that lead to stimulation of adenylyl cyclase and the subsequent secretion of salt and water leading to fatal diarrhea. 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 33

33. Two other diseases involve defective termination through mutations in G(s) protein a subunits, including; Adenomas , in which G proteins lose their ability to hydrolyze GTP through mutation, resulting in the excessive secretion of growth hormone and the increased proliferation of somatotrophs . McCune-Albright Syndrome , where scattered regions of skin hyper-pigmentation arise from the hyper-functioning of one or more endocrine glands. 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 34

34. 4b. RECEPTORS WITH KINASE ACTIVITY; A   kinase  is a type of enzyme that transfers  phosphate  groups from high-energy donor molecules, such as  ATP  (see below) to specific target molecules ( substrates ); the process is termed  phosphorylation . For every phosphorylation event, there is a phosphatase , an enzyme that can remove phosphate residue and thus modulate signaling Kinase enzymes that specifically phosphorylate tyrosine amino acids are termed  tyrosine kinases . 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 35

35. 1. RECEPTOR TYROSINE KINASE(RTKs) It is a cell surface receptor that also has a tyrosine kinase activity. The   signal binding domain   of the receptor tyrosine kinase is on the  cell surface ,  while the  tyrosine kinase enzymatic activity resides in the  cytoplasmic part of the protein . 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 36

36. A transmembrane alpha helix connects these two regions of the receptor. As is the case with GPCRs, proteins that bind GTP play a major role in signal transduction from the activated RTK into the cell. In this case, the G proteins are members of the Ras , Rho , and Raf families, referred to collectively as   small G proteins 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 37

37. The most important groups of signals that bind to receptor tyrosine kinases are: peptide growth factors  like nerve growth factor (NGF) and epidermal growth factor (EGF) peptide hormones , like insulin. Binding of signal molecules to the extracellular domains of receptor tyrosine kinase molecules causes two receptor molecules to  dimerize . This brings the cytoplasmic tails of the receptors close to each other and causes the tyrosine kinase activity of these tails to be turned on . 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 38

38. The activated tails then phosphorylate  each other  on several tyrosine residues. This is called autophosphorylation . The phosphorylation of tyrosines on the receptor tails triggers the  assembly of an intracellular signaling complex  on the tails. The newly phosphorylated tyrosines serve as binding sites for a variety of signaling proteins that then pass the message on to yet other proteins . An important protein that is subsequently activated by the signaling complexes on the receptor tyrosine kinases is called  RAS . 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 39

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41. The RAS protein has the following important features : 1 .  It is associated with the cytosolic face of the plasma membrane 2.  It is a   monomeric GTP-binding protein  (in fact, it is a lot like the alpha subunit of trimeric G-proteins). 3.  Just like the alpha subunit of a G-protein, Ras is active when GTP is bound to it and inactive when GDP is bound to it. Like the a subunit, Ras can hydrolyze the GTP to GDP This excited signal-emitting state is short-lived , however, because the intrinsic ( GTPase) activity of RAS hydrolyzes GTP to GDP, returning the protein to its quiescent GDP-bound state 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 42

42. Activated  RAS triggers a phosphorylation cascade   of protein kinases , which relay and distribute the signal. 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 43

43. These protein kinases are members of a group called the MAP kinases ( Mitogen Activated Protein Kinases ). The final kinase in this cascade phosphorylates various target proteins, including transcriptional activators ( e.g.myc ) that regulate gene expression . RAS is the most commonly mutated proto-oncogene in human tumors. Indeed, approximately 30% of all human tumors contain mutated versions of the RAS gene, and the frequency is even higher in some specific cancers (e.g., colon and pancreatic adenocarcinomas). 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 44

44. 2. NON RECPETOR TYROSINE KINASE (nRTKs) Non-receptor tyrosine kinases are a subgroup of protein family  tyrosine kinases , enzymes that can transfer the phosphate group from ATP to a tyrosine residue of a protein (phosphorylation ). Unlike the  receptor tyrosine kinases  (RTKs), the second subgroup of tyrosine kinases, the non-receptor tyrosine kinases are cytoplasmic enzymes . nRTKs regulate cell's growth, proliferation, differentiation, adhesion, migration and apoptosis and they are critical components in the regulation of the immune system. 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 45

45. The main function of nRTKs is their involvement in signal transduction in activated T- and B-cells in the immune system . CD4  and  CD8  receptors on T lymphocytes require for their signaling the  Src  family member  Lck . Src , cellular homolog of transforming protein of Rous Sarcoma Virus , is prototype for an important family of such nRTKs 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 46

46. Src contains unique functional regions such as Src-homology 2 ( SH2 ) and Src- homology 3 (SH3). SH2 domains typically bind to receptors phosphorylated by another kinase, allowing the aggregation of multiple enzymes. SH3 domains mediate other protein-protein interactions. 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 47

47. JAK-STAT Signaling pathway The   JAK-STAT signaling pathway  transmits information from chemical signals outside the cell, through the cell membrane, and into gene promoters on the DNA in the cell nucleus, which causes DNA transcription and activity in the cell. The JAK-STAT system is a major signaling alternative to the   second messenger system and is an example of nRTK . The JAK-STAT system consists of three main components: 1. a receptor 2. Janus kinase (JAK) and 3. Signal Transducer and Activator of Transcription (STAT). 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 48

48. Many JAK-STAT pathways are expressed in white blood cells, and are therefore involved in regulation of the immune system. MECHANISM. The binding of the ligand  to the receptor triggers activation of JAKs . With increased kinase activity, they phosphorylate  tyrosine residues on the receptor and create sites for interaction with proteins that contain  phosphotyrosine-binding SH2 domains . 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 49

49. STATs possessing SH2 domains capable of binding these phosphotyrosine residues are recruited to the receptors, and are themselves tyrosine-phosphorylated by JAKs These phosphotyrosines then act as binding sites for SH2 domains of other STATs, mediating their dimerization. Different STATs form hetero-  or homodimers. Activated STAT dimers accumulate in the cell nucleus and activate transcription of their target genes 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 50

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51. JAK-STAT pathway mutations are associated with many hematological malignancies caused by gaining constitutive functions e.g. MYELOPROLIFERATIVE NEOPLASMS ; Ph negative MPNs MDS MULTIPLE MYELOMA. 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 52

52. 4c. INTEGRINS Integrins are produced by a wide variety of cells; they play a role in: 1. Cell attachment to other cells and the extracellular matrix  and 2. 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 . 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 53

53. 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 . Integrin signaling exist in two places mainly; Integrin-signaling in circulating blood cells and non-circulating cells such as epithelial cells. 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 54

54. Important differences exist between two is that 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 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 55

55. 4c. TOLL GATE RECEPTORS Toll-like receptors  ( TLRs ) are a class of proteins that play a key role in the innate immune system. TLRs are a type of   pattern recognition receptor   (PRR) and recognize molecules that are broadly shared by pathogens but distinguishable from host molecules, collectively referred to as  pathogen-associated molecular patterns  (PAMPs). 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 56

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57. 4e. LIGAND-GATED ION CHANNEL Ligand-gated ion channels (LGICs) are a group of transmembrane ion channel proteins which open to allow ions such as  Na + , K + ,Ca 2+ , or  Cl −  to pass through the membrane in response to the binding of a chemical messenger (i.e. a  ligand ),  such as a neurotransmitter. 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. 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 58

58. 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 . Ligand-gated ion channels  are likely to be the major site at which anaesthetic agents and ethanol have their effects, in particular, the  GABA  and  NMDA  receptors are affected by anaesthetic  agents. 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 59

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60. 5. INTRACELLULAR RECEPTORS Intracellular receptors  are receptors located inside the cell rather than on its cell membrane . Classic hormones that use intracellular receptors include thyroid and steroid hormones. Examples are: Class of  nuclear receptors  located in the cell nucleus   and   cytoplasm  IP 3  receptor  located on the endoplasmic reticulum . 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 61

61. The ligands that bind to them are usually: Intracellular  second messengers  like  inositol trisphosphate  (IP 3 ) Extracellular  lipophilic hormones  like steroid hormones. 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. 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 62

62. All hormones that act by regulation of gene expression have two consequences in their mechanism of action ; 1. their effects are produced after a characteristically long period of time 2. 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. E.g. Thyroid Hormone 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 63

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65. CONCLUSION The entire signal transduction system normally works astonishingly well, but serious problems can occur. Cancer is unregulated cell growth and occurs when the machinery tightly regulating cell growth breaks down. Mutations in growth factor receptors, G proteins, MAP kinases , and other molecules frequently contribute to cancer, and generally result in these molecules losing their normal switching function, staying in the activated form and therefore inappropriately stimulating these important enzyme cascades. 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 66

66. The complexity of the signaling system makes for challenging research, but once understood it holds the promise for better treatments for cancer and other diseases. This is because each step in each pathway provides one or more targets for drugs. Designing a drug that could quiet the excess signaling caused by defective MAP kinase , for example, might provide a promising cancer treatment . 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 67

67. The examples given thus far provide only an outline of how signal transduction cascades work and an overview of a few of the most important enzymes. The actual process is much more complex, and there is much about the process that remains mysterious. Perhaps the biggest mystery is how the cell makes sense of all of the input from different growth factors, hormones, extracellular substrates, and so on to produce an appropriate response. 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 68

68. The solution to this problem will result from a complete understanding and computer modeling of the biochemical and kinetic properties of the components of all these signaling cascades . _______________________.____________________________ 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 69

69. 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 70 THANK YOU

70. REFRENCES 1. KUMAR, ABBAS AND COTRAN, ROBBINS BASIC PATHOLOGY OF DISEASES, NINTH EDITION 2. GUYTON AND HALL, TEXT BOOK OF MEDICAL PHYSIOLOGY, ELEVENTH EDITION. 3. KIM E BARRET, SUSAN M BARMAN, SCOT BIOTANO,GANONG’S MDEICAL PHYSIOLOGY, TWENTY THIRD EDITION. 4. INTERNET SOURCES. 19-Jan-16 SIGNAL TRANSDUCTION MECHANISMS 71