CELL TISSUE ORGAN Heart Brain stomach ORGANISM SYSTEM

CELL TISSUE ORGAN Heart Brain stomach ORGANISM SYSTEM CARDIOVASCULAR NERVOUS GASTROINTESTINAL

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

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

CELL-TO-CELL COMMUNICATION

Modes of signal transduction between different cell types

Types of cellular receptors

INTERACTION BETWEEN SIGNALING PATHWAYS: SIMILARITIES TO NEURAL NETWORKS?

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.

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.

Schematic representation of cross-talk between signaling pathways

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).

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.

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.

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

HOMEOSTATIC MEDIATORS Hormones Cytokines Neurotransmitters Growth Factors

NUCLEAR RECEPTORS Early response Delayed response

THE NUCLEAR RECEPTORS SUPERFAMILY

Glucocorticoid Receptor Signaling Ligand Cell Membrane Ligand Binding GR Import HSPs Nucleus Transactivation /Transrepression Assembly TF Export GREs m. RNA 1 TFE m. RNA 2

Transcriptional Activation by GR through Interaction with Multiple Protein Complexes SWI/SNF Histone Acetyltransferases DRIP/TRAP p 300/CBP p/CAF p 160 Transcription initiation complex AF 2 AF 1 GR GR Coactivation RNA polymerase II AF 1 Chromatin modulation GREs Transcription

Non – nuclear receptor families

MODES OF SIGNALING

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

C. Enzyme-linked receptors

IL-2: an example of a cytokine receptor

Schematic representation of cross-talk between signaling pathways

MOLECULAR MEDIATORS OF ENERGY HOMEOSTASIS Neuropeptides * Agouti protein * a-MSH (a-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

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 c. AMP in the cytosol. c. AMP acts inside the cell to alter the rate of process(es).

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

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.

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

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

Early thoughts: neuronal contributions to various bodily functions could be localized to discrete brain regions or centers. Experiment (1940 s): 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

In the hypothalamus: LHA controls hunger VMN controls satiety

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

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

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

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.

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