1. Φυσιολογία 1η διάλεξη 13/11/2009 Κάτια Καραλή Ερευνήτρια Β, ΙΙΒΕΑΑ

2. CELL TISSUEORGAN Heart Brain stomach SYSTEM ORGANISM CARDIOVASCULAR NERVOUS GASTROINTESTINAL

3. CELL COMMUNICATION physical electrical chemical neurotransmitters hormones Receptor Signaling pathway Gene transcription FUNCTION

4. SERIAL ACTIVATION COMBINED ACTIVATION and INHIBITION TRANSCIPTIONAL REGULATION TRANSLATIONAL REGULATION POSTTRANSLATIONAL MODIFICATION

5. CELL-TO-CELL COMMUNICATION

6. Modes of signal transduction between different cell types

7. Types of cellular receptors

13. INTERACTION BETWEEN SIGNALING PATHWAYS: SIMILARITIES TO NEURAL NETWORKS?

14. A simple neural network. The activity of each neural unit (shown as a circle) is determined by the unit's inputs. The output of each unit is usually a nonlinear function of the unit's inputs. Each connection between units has a particular strength, or "weight," which is indicated by differences in thickness of the connecting arrows.

15. A simple hypothetical signaling network. The network consists of six receptors and three cytosolic protein kinases. Each receptor activates ( green arrows) or inhibits ( black lines) kinase 1 or 2 or both by an unspecified mechanism. Because signals converge onto kinase 3 (the output kinase), this network will be maximally active only when specific combinations of extracellular stimuli are present. Although this network is far simpler than any likely to be found in a living cell, it could form part of a more complex signaling pathway.

16. Schematic representation of cross-talk between signaling pathways

17. PHYSIOME The quantitative and integrated description of the Functional behavior of the physiological state of an individual or species. The physiome describes the physiological dynamics of the normal intact organism Is built upon information and structure (genome, proteome, morphome).

18. PHYSIOME In its broadest sense, the physiome should define relationships from genome to organism and from functional behavior to gene regulation. The Physiome Project includes integrated models of components of organisms, such as particular organs or cell systems, biochemical or endocrine systems.

19. Physiome Project : Compiles and provides a central repository of databases, linking experimental information and computational models into a single, self-consistent framework. -----> it aims to promote comprehensive databases and an integrative, analytical approach to the study of medicine.

20. BODY SYSTEMS Skeletal and Muscle Gastrointestinal (Digestive) Circulatory and Respiratory Urinary Reproductive Nervous Endocrine

21. HOMEOSTATIC MEDIATORS Hormones Cytokines Neuro- transmitters Growth Factors

23. NUCLEAR RECEPTORS Early response Delayed response

24. THE NUCLEAR RECEPTORS SUPERFAMILY

26. Glucocorticoid Receptor Signaling Nucleus Cell Membrane HSPs GREs Ligand GR Import Ligand Binding Assembly Export TF TFE Transactivation /Transrepression mRNA1 mRNA2

27. Transcriptional Activation by GR through Interaction with Multiple Protein Complexes Histone Acetyltransferases AF1 AF2 SWI/SNFDRIP/TRAP p300/CBP p160 p/CAF AF1 Transcription initiation complex Coactivation Chromatin modulation RNA polymerase II Transcription GREs GR

28. Non – nuclear receptor families

33. MODES OF SIGNALING

34. Typical structure of a G-protein coupled receptor (GPCR)

35. C. Enzyme-linked receptors

43. IL-2: an example of a cytokine receptor

45. Schematic representation of cross-talk between signaling pathways

47. MOLECULAR MEDIATORS OF ENERGY HOMEOSTASIS Neuropeptides * Agouti protein *  -MSH (  -Melanocyte stimulating hormone) * Cocaine- and amphetamine –regulated transcript (Cart) * Hypocretin (or Orexin) 1 and 2 * MCH (melanin-concentrating hormone) * NPY (neuropeptide Y) * TRH (thyrotropin-releasing hormone) Peripheral molecules * Leptin * CCK (cholecystokinin) * Ghrelin * Insulin

48. Combination of a receptor with the hormone (ligand) leads to activation of adenylate cyclase bound also to the membrane. Increased activity of adenylate cyclase increases cAMP in the cytosol. cAMP acts inside the cell to alter the rate of process(es).

49. Endocrine system Hormones are synthesized by glands Secreted directly into the blood and carried to their sites of action Specifically alter the activities of responsive tissues

50. HORMONES: Chemical substances liberated by specific cell types carried by the bloodstream to act on distant target cells. The cell membrane contains receptors for hormones.

51. HYPOTHALAMUS pituitary PHYSIOLOGICAL ACTIONS PERIPHERAL GLAND Central Nervous System Stimuli Releasing hormone Trophic hormone Hormone

52. GLAND DEGRADED response prohormone HORMONE receptor effector DEFECT STIMULATION Target cell TISSUE DAMAGE HYPOFUNCTIONHYPERFUNCTION Destruction block Tumor hyperplasia Ectopic production block stimulation block ANTIBODIES ANTAGONISTS ANTIBODIES

54. Early thoughts: neuronal contributions to various bodily functions could be localized to discrete brain regions or centers. Experiment (1940s): lesioning of the brain and evaluation of physiology following the distruction of specific areas. -bilateral lesioning of LHA  anorexia and weight loss -bilateral lesioning of VMN  obesity

55. In the hypothalamus: LHA controls hunger VMN controls satiety

57. Two classes of neurons involved in responses to leptin in the CNS: -depolarized-> anorexigenic peptides -hyperpolarized->orexigenic peptides

58. Npy increased by starvation not regulated by overfeeding Pomc / Cart increased by starvation decreased by overfeeding

61. Close this window to return to the previous window Box 1 Leptin- and insulin- recepto r signalli ng © 2000 Nature Publishing Group Privacy Policy Unlike insulin receptors, leptin receptors are members of the cytokine-receptor superfamily and do not have intrinsic tyrosine kinase activity 118. However, the leptin receptor does have docking sites for janus kinases (JAK), a family of tyrosine kinases involved in intracellular cytokine signalling 119. Activated JAK phosphorylates members of the signal transduction and transcription (STAT) family of intracellular proteins. STAT proteins, in turn, stimulate transcription of target genes that mediate some of leptin's cellular effects. Although regulation of hypothalamic neuropeptide gene expression by leptin is well described, the role of JAK–STAT signalling in this response remains uncertain, as leptin can affect neuronal firing rate independently of its transcriptional effects. For example, a subset of 'glucose-responsive' neurons in the hypothalamus become hyperpolarized (and therefore decrease their firing rate) within minutes of leptin application 120. Glucose influences the membrane potential of glucose-responsive neurons indirectly through its oxidation to generate ATP, which in turn controls the activity of ATP-sensitive potassium channels (K ATP ) in the plasma membrane 121. Closure of K ATP channels in response to increasing intracellular concentrations of ATP (relative to ADP) raises intracellular [K + ], which depolarizes the cell and increases its firing rate. Because leptin maintains K ATP channels in the open configuration 120, positively charged K + ions diffuse out of the cell and lower its membrane potential. This effect on K ATP channels can be detected even in isolated patches of plasma membrane, excluding a mechanism involving transcriptional effects of leptin. The relationships among leptin signalling through the JAK–STAT pathway, its effects on neuronal firing rate, and its control of neuropeptide gene expression are an important area for future study. Close this window to return to the previous window Box 1 Leptin- and insulin- recepto r signalli ng © 2000 Nature Publishing Group Privacy Policy Unlike insulin receptors, leptin receptors are members of the cytokine-receptor superfamily and do not have intrinsic tyrosine kinase activity 118. However, the leptin receptor does have docking sites for janus kinases (JAK), a family of tyrosine kinases involved in intracellular cytokine signalling 119. Activated JAK phosphorylates members of the signal transduction and transcription (STAT) family of intracellular proteins. STAT proteins, in turn, stimulate transcription of target genes that mediate some of leptin's cellular effects. Although regulation of hypothalamic neuropeptide gene expression by leptin is well described, the role of JAK–STAT signalling in this response remains uncertain, as leptin can affect neuronal firing rate independently of its transcriptional effects. For example, a subset of 'glucose-responsive' neurons in the hypothalamus become hyperpolarized (and therefore decrease their firing rate) within minutes of leptin application 120. Glucose influences the membrane potential of glucose-responsive neurons indirectly through its oxidation to generate ATP, which in turn controls Close this window to return to the previous window Box 1 Leptin- and insulin- recepto r signalli ng © 2000 Nature Publishing Group Privacy Policy

65. Leptin : an adipose tissue secreted hormone; the product of the ob gene. Its main physiological role is to signal nutritional status during periods of food deprivation

66. Insulin and leptin: Circulate at levels proportional to body fat content Enter the CNS in proportion to their plasma level Their respective receptors are expressed in neurons involved in energy intake Administration of either icv reduces food intake Deficiency of either or components of their signaling pathway increases food intake The above strongly support their function as adiposity signals.

70. OBESITY Metabolic rate Exercise Food intake Culture Monogenic disorders Susceptibility genes Genes Cardiovascular Endocrine Gastrointestinal Nervous