Lecture6

Lecture6 Environmental stresses Activation of •Molecular Mechanisms of Cell Signalling 2017

14/3/2017 By Prof.Dr /Ahmed Mansour Alzohairy

Genetics Department, Zagazig University, Zagazig, Egypt

Learning objectives Learning about activation of Environmental stresses Activation of cell signaling : Why do cells communicate How are signals transmitted between cells How are signals transmitted across cell membranes into cell interior How are signals transmitted within a cell How do signals affect a cell function Signal transduction Ion channels

Learning outcomes By the end of this session and practical, students are expected to be able to understand what are:

- complex system of communication. - Diseases based on Errors in cellular information processing - The difference between cell signaling and signal transduction

Disclaimer This lecture is based on a presentation entitled:

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INTRODUCTION: Cells must be ready to respond to essential signals in their environment. These are often chemicals in the extracellular fluid (ECF) from: distant locations - signaling by hormones; nearby cells  cytokines; or even secreted by themselves . Long-range allostery is often a significant component of cell signaling events. 5

CELL SIGNALING Cell signaling is part of a complex system of communication that governs basic cellular activities and coordinates cell actions. The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, tissue repair, and immunity as well as normal tissue homeostasis Errors in cellular information processing are responsible for diseases such as cancer, autoimmunity, and diabetes. By understanding cell signaling, diseases may be treated effectively and, theoretically, artificial tissues may be created. 6

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STEPS IN CELL SIGNALING SYNTHESIS OF SIGNALLING MOLECULES

RELEASE OF SIGNALLING MOLECULES

TRANSPORT OF SIGNAL TO TARGET CELLS

DETECTION & BINDING OF SIGNAL BY SPECIFIC RECEPTOR

CHANGES DUE TO RECEPTOR-SIGNAL COMPLEX

SIGNAL REMOVAL & RESPNOSE TERMINATION

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CLASSIFICATION OF INTERCELLULAR COMMUNICATION Intercellular signaling is subdivided into the following classifications: Autocrine signals target the cell itself. Sometimes autocrine cells can target cells close by if they are the same type of cell as the emitting cell. An example of this are immune cells.

Paracrine signals target cells in the vicinity of the emitting cell. neurotransmitters represent an example. Endocrine signals target distant cells. Endocrine cells produce hormones that travel through the blood to reach all parts of the body. Juxtacrine signals target adjacent (touching) cells. These signals are transmitted along cell membranes via protein or lipid components integral to the membrane and are capable of affecting either the emitting cell or cells immediately adjacent.

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Autocrine signals target the cell itself. Sometimes autocrine cells can target cells close by if they are the same type of cell as the emitting cell. An example of this are immune cells.

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Paracrine signals target cells in the vicinity of the emitting cell. neurotransmitters represent an example.

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Endocrine signals target distant cells. Endocrine cells produce hormones that travel through the blood to reach all parts of the body.

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JUXTACRINE SIGNALING Juxtacrine signals target adjacent (touching) cells. These signals are transmitted along cell membranes via protein or lipid components integral to the membrane and are capable of affecting either the emitting cell or cells immediately adjacent.

MEMBRANE-ANCHORED LIGANDS

e.g.*Notch signalling.

NEIGHBOURING CELLS

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Ion Channels

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Schematic diagram of an ion channel 1 - Channel domains(typically four per channel), 2 - Outer vestibule, 3 - Selectivity filter, 4 - Diameter of selectivity filter, 5 - Phosphorylation site, 6 - Cell membrane.

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Cell membrane

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Membrane transport proteins

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Ion channels are not pumps Only ion channels have an aqueous pore that crosses the membrane

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Channels are made up of subunits

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Ion channels are made from 2-6 similar proteins or homologous structural units ‐ PORE-FORMING SUBUNITS - they associate creating the functional ion channel In addition, many channels contain the auxiliary regulatory subunits 37

Channels are made up of subunits

• Pore-forming subunits contain an a‐helix made by ~20 hydrophobic amino acids which interact with the annular phospholipids of the lipid bilayer

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Ion channel types (by gating)

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Ligand-gated channels Typically, these are ion channels located on the postsynaptic (receiving) side of the neuron

Some act in response to a secreted (external) ligand- typically a neurotransmitter such as • Acetylcholine (ACh) • GABA • Glycine • Glutamate Some act in response to internal ligands such as G-proteins, cGMP and cAMP, and are also regulated by internal metabolites such as phosphoinositides, arachidonic acid, calcium.

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Signal-gated channels Atrial m2 receptor-G proteincoupled K+ channels

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Modifiers of Channel Gating (curare) (alphabungarotoxin) (ACh)

Binding of exogenous ligands can block gating

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Modifiers of Channel Gating

Ion permeation can be prevented by pore blockers, e.g. voltage-dependent block of NMDARs by Mg2+

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Modifiers of Channel Gating Current Time

Open

Closed

Open

Closed

Exogenous modulators can modify the action of endogenous ligands 44

Bu Z, Callaway DJ (2011). "Proteins MOVE! Protein dynamics and long-range allostery in cell signaling". Advances in Protein Chemistry and Structural Biology. Advances in Protein Chemistry and Structural Biology 83: 163–221. Rang & Dale's Pharmacology

http://en.wikipedia.org/wiki/Cell_signaling http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/C/CellSignaling.html www.authorstream.com/.../shona6685-645587-ppt-cell-signaling

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC151254/  Congreve M, Marshall F (March 2010). "The impact of GPCR structures on pharmacology and structure-based drug design". Br. J. Pharmacol. 159 (5): 986–96.doi:10.1111/j.1476-5381.2009.00476x PMC 2839258 PMID19912230 45

Molecular Genetics I: MLGN 301 2016 Trainer name: Prof. Ahmed Mansour Alzohairy

Molecular Genetics I: MLGN 301 2016 Trainer name: Prof. Ahmed Mansour Alzohairy

Molecular Genetics I: MLGN 301 2016 Trainer name: Prof. Ahmed Mansour Alzohairy

Molecular Genetics I: MLGN 301 2016 Trainer name: Prof. Ahmed Mansour Alzohairy

Department of Genetics, Zagazig University, Zagazig, Egypt