CELL SIGNALIING AND MECHANISMS OF ACTION OF HORMONES 2022.pptx

A BRIEF INTROCUCTION ON CELL SIGNALLING

1. CELLULAR SIGNALLING AND MECHANISMS OF ACTION OF HORMONES YEAR 11 MB CH B HABIB MEDICAL SCHOOL DR JOSHUA TUGUMISIRIZE Ph D AUGUST 2022

2. INTRODUCTION TO CELL SIGNALLING 1 KEY WORDS First messenger Second messenger Transduction Transcription

3. COMMUNICATION BETWEEN CELLS Communication between cells can be: direct : cell to cell indirect : neurotransmitters or hormones Technically the message from one cell to another is ‘the signal’. We may also refer to the signal as a stimulus.

4. NATURE OF THE SIGNALS The signals (stimuli) may come from the environment or from within the body (organism) The signals can be PHYSICAL or CHEMICAL Examples of physical stimuli: sound, heat, light, touch, pressure, Examples of chemical stimuli:, gases, odours, acid, glucose , proteins, hormones, neurotransmitters

5. MECHANISM OF CELL SIGNALLING There must be a signal/stimulus The signal must travel from the source to the receiver – the target cell The target cell has a special structure specific to the signal: the receptor The stimulus interacts with the receptors in specific manner in order to produce a response ( this is referred to as TRANSDUCTION’.

6. MODES OF INTERCELLULAR SIGNALING 1

7. NEURO-ENDOCRINE

8. SUMMARY OF CHEMICAL MEDIATORS

9. MODES OF INTERCELLULAR SIGNALING 1 Example 1 Nervous signalling: involves rapid transmission of action potential, often over long distances. Neurotransmitter is released at a synapse., Specific receptors are on muscles and glands and other tissues

10. MODES OF INTERCELLULAR SIGNALING 2 Example 2 Endocrine signalling involves release of hormone into blood stream and binding of hormones on specific target cell receptors

11. LOCAL HORMONES Nitric oxide GIT hormones Strictly speaking, these do not fit the classical definition of a hormone. All the same, they act of membrane proteins or receptors

12. MODES OF INTERCELLULAR SIGNALING 3 Example 3 Neuroendocrine signalling involves release of hormone from a nerve cell and transport of the hormone in the blood stream to a distant cell target. In the case of the adrenal medulla, the neurotransmitter (noradrenaline) acts locally

13. NEUROTRANSMITTERS AND HORMONES Neurotransmitters and hormones are the main chemical messengers. They provide coordination and integration of activities among cells in the body, locally and at great distances The neurotransmitters from the nervous system and hormones from the endocrine system are specially adapted to provide coordination and integration of activities locally and at distant locations in the body.

14. HORMONES Hormones are principally neuropeptides . Hypothalamic –releasing hormones Pituitary peptides: prolactin , Vasopressin, Oxytocin , Peptides that act on gut and brain: substance P, cholecystokinin , insulin, Glucagon There are non-peptide chemical messengers mainly from tissues and act locally eg bradykinin, eicosanoids (e g prostaglandins); gases e g nitric oxide; ions like H+

15. RECEPTORS Receptors are specialized portions of the plasma membrane or molecules within the cytoplasm or nucleus. There is a diverse variety of receptors

16. CLASSIFICATION OF RECEPTORS 1 Ion channels ( ionotropic ) 2 G protein –coupled receptors ( metabotropic ) 3 Catalytic enzymes within the plasma membrane 4 Nuclear receptors:-regulatory sequences in DNA. All classical neurotransmitters and neuropeptides have at least one metabotropic type receptor

17. NATURE OF RECEPTORS 1 Voltage –gated ion channels: entry of cations into cell produce change in membrane potential (ion pore) 2 Catalytic receptor- membrane bound enzyme: protein kinases G protein-coupled receptor- change in intracellular chemicals – second messengers 4 Cytoplasmic /intracellular receptors: gene transcription: activation of nuclear receptors

18. HORMONE RECEPTORS Each hormone has a specific receptor Receptors are found on cell surface or in cytoplasm or within the nucleus There are 2000- 100,000 receptors Surface receptors are receptors for mainly proteins , peptides and catecholamines . Receptors for s teroid hormones are found in cytoplasm and in the nucleus Receptors for thyroid hormones are found in the nucleus.

19. METABOTROPIC RECEPTOR The main example is the G –protein coupled receptor. The hormones (ligands) attach on the outside membrane and induce conformational change which activates the intracellular binding site of the G protein The transduction process involves a cascade of reactions that leads to a variety of responses The process is slow and prolonged for minutes or hours

20. G PROTEIN-LINKED RECEPTORS In the majority of cases an external stimulus will act on a receptor on the plasma membrane. The response to the stimulus is specific. It may be immediate or delayed Response to first messenger is immediate and mainly involves ion channels In the case of G protein-coupled receptors, there are intermediate processes to produce second messengers which cause the desired output.. E g cAMP , cGMP , inositol triphosphate (IP3), Diacylglycerol (DAG); Ca++

21. NUCLEAR RECEPTORS These are receptors for steroid hormones ( minerocorticoids , glucocorticoids, androgens, Estrogens, progestins ) plus thyroid hormones and vitamin D, These hormones produces their effects by binding to regulatory sequences in DNA and - increase or decrease gene transcription

22. FIRST MESSENGERS AND cAMP

23. LIGANDS TO G PROTEINS 2

24. TYPES OF SECOND MESSENGERS The first messengers are hormones. The second messengers are synthesised as a result of first messenger activation of specific receptors: (regulate target proteins) Cyclic AMP, Cyclic GMP Kinases , phosphatases Calcium ions: calcium- calmodulin Complex. Inositol triphosphate -IP3 Diacylgylcerol (DAG)

25. TRANSDUCTION Transduction is the process by which a stimulus is converted into a response Usually an adequate stimulus will activate a specific receptor All receptors are proteins!- located in the plasma membrane, cytoplasm and the nucleus. Proteins are either enzymes in the membrane or ion channels. The message is some cases is passed from one protein to another

26. RESPONSE TO HORMONE ACTION A variety of response to hormone action include: -secretion -metabolism -cell-cycle control -survival -proliferation -motility differentiation

27. TRANSDUCTION

28. SECOND MESSENGERS 2 There a huge range of G protein coupled receptors (GPCRS): more than 1000 receptors There is also a family of enzymes that modulate a variety of signalling pathways: Proetin kinase A Phospholipase C Phospholipase A2, C, D

29. FUNCTIONS OF SECOND MESSENGERS The serve to amplify responses to the ligand through activation of the G protein receptor complex As a result, there are multiple cellular processes ( a cascade of chemical reactions) that comprise of the response to the second messengers The second messengers produce a diverse range of proteins e g transport proteins, metabolic enzymes, gene replicating proteins, cytoskeletal proteins and cell cycle proteins. The final responses include altered ion transport, altered metabolism, altered gene expression, altered cell shape and movement and altered cell growth and division.

30. THE HORMONE-G PROTEIN COMPLEX

31. EXAMPLE 1

32. EXAMPLE 2

33. cAMP - THE SECOND MESSENGER

34. SECOND MESSENGER SYSTEM

35. FIRST MESSENGER /PHOSPHOLIPASE C

36. PHOSPHOLIPID SECONDER MESSENGER SYSTEM

37. THE PHOSPHOLIPASE C PATHWAY

38. Ca++- CALMODULIN Calcium- calmodulin is an important second messenger system It operates by opening of ca++ channels (membrane ion channels) -Ca++ bind with protein – calmodulin (four calcium binding sites) Ca++- calmodulin complex either activates or inhibits protein kinases Change in Ca++ Conc : 10 (-8 t0-7) to 10 (- to -5)Ca

39. BALANCE EXCITATION AND INHIBITION

40. A KINASE A kinase is an enzyme that adds a phosphate group to a substrate eg insulin is receptor tyrosine kinase

41. TYROSINE KINASES These are enzymes within the cell membrane For example the receptor tyrosine kinase mediates the response to growth hormone and insulin There are also catalytic receptors which are membrane bound protein kinases Insulin receptors are found in liver, muscle fibres and fat cells. The tyrosine kinases activate other enzymes by adding a phosphate to tyrosine residues. Other examples are: epidermal growth factor (EGFR), Platelet-derived growth factor receptor (PDGFR).

42. THE HORMONES THAT USE RECEPTOR TYROSINE KINASE SIGNALING

43. TYROSINE KINASE RECEPTORS

44. HORMONE –RECEPTOR COMPLEX

45. EXAMPLE 4: ENZYME LINKED RECEPTOR

46. ABOUT LEPTIN Leptin is a hormone secreted by fat It is important in regulating appetite and energy balance Leptin receptor belongs to the family of CYCTOKINE receptors The signal is through associated enzymes to cytokines ie tyrosine kinase of the JANUSKINASE (JAK) family

47. PHYSIOLOGICAL RESPONSE The response to the metabotropic receptors includes -secretions -movement -cellular growth and cell division - and even cell death (apoptosis)

48. EXAMPLE 5: NITRIC OXIDE

49. EXAMPLES OF SECOND MESSENGERS ( Metabotropic - receptor does not have ion channel) The alpha subunit of the G protein activates the adenylyl cyclase This serves a catalyst for production of cAMP cAMP acts a second messenger Opening of ion channel – Na+, Ca++ influx

50. EXAMPLES OF SECOND MESSENGERS Calcium- calmodulin complex: smooth muscle contaction Phospholipase A2: Arachidonic acid – produce: prostaglandin, leuokotrienes Serotonin – reported to activate at least 15 G protein –coupled receptors. Bacteria toxins has been shown to activate the alpha subunit of G protein in cholera and whooping cough

51. EXAMPLES 6

52. cAMP Most widely distributed second messenger: smooth muscle, sensory cells Activates protein kinase A (PKA) Catalyzes phosphorylation of cellular proteins (ion channels) Phosphorylation alters the function of ion channel cAMP involved in formation of memories.

53. THE cAMP SYSTEM

54. Ca++ AS SECOND MESSANGER Calcium- calmodulin –dependent protein kinase Release of calcium from internal stores (Endoplasmic reticulum) E g muscle cells Basis for long term potentiation

55. INOSITOL TRIPHOSPHATE IP3

56. PHOSPHOLIPASE C PATHWAY 2

57. DYSREGULATION OF CELL SIGNALLING AND DISEASE Disorders of cell signalling are the origin of disease 1 Cancer 2 Epilepsy 3 endocrine disorder 4 movement disorders

58. SUMMARY Chemical communication can be by neurotransmitters, amino acids peptides, steroid hormones and metabolites Chemical messengers act through a variety of receptors Physiological effects of chemical signals are variety: change in membrane potentials, secretions, movements, gene transcription, growth and cell division, inflammation and immune reactions

59. QUESTIONS What are the physical characteristics of chemical signals? Explain the terms: receptor, ligand , voltage-gated channel. What is the process of transduction? What do you understand by ‘second messenger system?