Cell communication lecture.pptx

Life Sciences Receptors and signaling Dr Ramin Farahani School of Medical Sciences Acknowledgments Dr Jinlong Gao The University of Sydney Page 1  Learning Objectives – Describe the general steps of intercellular signalling – Describe the different types of cell signals – Distinguish between...

Life Sciences Receptors and signaling Dr Ramin Farahani School of Medical Sciences Acknowledgments Dr Jinlong Gao The University of Sydney Page 1  Learning Objectives – Describe the general steps of intercellular signalling – Describe the different types of cell signals – Distinguish between endocrine, paracrine and autocrine signalling – Briefly discuss the intracellular signalling system and define the role of second messengers The University of Page 2 Sydney  Membrane Proteins – Transport proteins – Enzymes – Intercellular junctions – Cell-cell recognition – Receptors – Adhesion to extracellular Page 3 matrix The University of Sydney  Membrane –Receptors Binding the signal or ligand – Produce a second signal / second messenger which causes a cellular response – Some signals can cross the membrane – bind receptor in cytoplasm. The University of Page 4 Sydney  Cell signalling Why do cells need receptors and signalling systems? – Respond to changes in their immediate environment – Cell communication – Coordinated control of cellular functions – Intercellular signalling – communication between cells – Intracellular signalling – within the cells, responding to extracellular and intracellular stimuli The University of Page 5 Sydney  Intercellular Communication – Between cells – Upon reception of a triggering stimulus the signal is transformed into a chemical or electrical messenger within the signalling cell. – The messenger is secreted and transported to the target cell. – In the target cell, the messenger is recognised, transmitted and converted into a biochemical reaction. The University of Page 6 Sydney  Types of – Signalling Direct – Direct cell to cell signalling (Gap Junctions) – i.e. conductance between heart smooth muscle – Chemical: Signalling by secreted molecules – Endocrine – Paracrine (including synaptic) – Autocrine The University of Page 7 Sydney  Direct signalling – A transfer of ions or small molecules from one cell to its neighbour cell – Allow electrical signal transduction – Through pores in the membrane – Gap junctions – Fastest mode of cell to cell communication – i.e. heart, neuron, retina The University of Page 8 Sydney  Gap Junction › Connexon - Transmembrane s protein wide - iTghtly packed 7 hollow nm cylinder - form a 3 nm thin hydrophilic channel - No leaking - Facilitate direct communication between cells of signalling molecules (ATP, cAMP, IP3, Na+, K+, Ca2+…) The University of Page 9 Sydney  Endocrine – Signalling Q: What is the signal? – A: Hormones produced by an endocrine gland - Lipophilic molecules (i.e. progesterone, testosterone) - Hydrophilc molecules – plasma membrane receptors (i.e. insulin, glucagon, thyroxine) – Q: How to get the target cells? – A: Travel through the blood stream to distant cells – Q: How does the cell receive the signal? – A: Surface receptors (most protein and peptide hormones) and intracellular receptors (steroid hormones) The University of Page Sydney 10  Paracrine Signalling › Q: What is the signal? › A: Similar to hormones but do not enter the blood circulation. › They are also rapidly destroyed by extracellular enzymes or bound to extracellular matrix – to prevent widespread diffusion › Q: How to get the target cells? › A: Travel to nearby cells in which the gradient of signal molecule received determines the outcome. The exact distance is not certain. › Q: How does the target cell receive the signal? The University of Page Sydney 11  Synaptic Signalling – A special case of paracrine signalling – A special structure is involved – Synapse (between the cell originating and the cell receiving the signal) – Only occurs between cells with the synapse – i.e. between neuron cell - effectors The University of Page Sydney 12  Autocrine Signalling › Q: What is the signal? › A: Signal molecules secreted by the target cell, e.g. prostaglandins. › Q: What is the difference between autocrine, paracrine, and endocrine? The University of Page Sydney 13  How do cells respond to signals? Response: - Receptor protein received signal - Undergoes conformational change - Launches a series of biochemical reactions within the cell - Signal transduction cascades - Amplify message - Multiple intracellular signals - Can trigger synthesis of The University of Sydney second messengersPage 14  Types of Receptors – Ion-channel receptors – Ligand-gated channel – Receptors with intrinsic or associated enzymatic activity – Ligand activates the catalytic activity of the receptor – Activate an effector protein – G protein-coupled receptors – Ligand causes conformation change – Activate a G protein The University of Page – Activate an effector Sydney 15  G Protein-Coupled Receptors / GPCRs – GPCRs – Integral membrane protein – Contain 7 transmembrane regions – N-terminus on the exoplasmic face – C-terminus on the cytosolic face – Ligand specific – Bound to G-protein The University of Page Sydney 16 What is G protein? – Heterotrimeric proteins – In the inactive state, Gα binds to GDP – Interaction between Gα and stimulated receptor causes the release of GDP – GTP then binds to the empty site because its concentration in the cell is higher than GDP. – The GTP-bound Gα has low affinity to βγ subunits, resulting in their dissociation. – GTP is hydrolysed to GDP because Gα as GTPase activity. The University Sydney of Page 17  GPCR Signalling System – How does it work? – Activate the receptor via ligand binding – Activates the G protein – Activate an effector enzyme to generate an intracellular second messenger The University of Page Sydney 18  Intracellular signalling and second messenger – Intracellular signalling – within the cells, responding to extracellular and intracellular stimuli – Second messenger – A substance that is released in the cytoplasm following activation of a receptor – Relay the information from the first messenger (hormones / signal molecules) – Non-specific – Generate a variety of responses in the cell The University of Page Sydney 19  Second Messenger – cyclic nucleotides cAMP (cyclic adenosine monophosphate) – Extracellular signals: Adrenaline, glucagon, luteinizing hormone etc. – Synthesized by adenylyl cyclase which is controlled by different G proteins – Active protein kinase A – Phosphorylation of target proteins The University of Page Sydney 20  What is protein kinase? – Add phosphate groups to themselves/other proteins when active – Opposed by phosphatases which remove phosphate groups from specific phosphorylated proteins – Nobel Prize for Medicine and Physiology 1992 for their discoveries of reversible protein phosphorylation Prof Edmond H. Fischer Prof Edwin G. Krebs The University of Page Sydney 21  Second Messenger – Ca2+ – An important intracellular signal – Low cytosol concentration – Response to electrical or intracellular chemical signal – Ca2+ pump – out of the cells or into the ER – Calcium-binding protein Calmodulin – Exocytosis, muscle contraction, mitosis The University of Page Sydney 22  Could you try to Second Messenger: Ca 2+ explain this signalling system by yourself? The University of Page Sydney 23