cell signaling

PRESENTED BYPRESENTED BY

V.Prem PrasadV.Prem PrasadM.Pharmacy 1M.Pharmacy 1ststYear(pharmacology)Year(pharmacology)

Gokaraju rangaraju college of pharmacyGokaraju rangaraju college of pharmacy 1

CONTENTS

IntroductionIntroduction Modes of cell signalingModes of cell signaling Communication between cellsCommunication between cells Signal transduction Signal transduction Ion channelsIon channels

2

INTRODUCTION:Cells must be ready to respond to essential signals in their Cells must be ready to respond to essential signals in their environment. These are often chemicals in the extracellular fluid (ECF) environment. These are often chemicals in the extracellular fluid (ECF) from: from:

distant locations -distant locations - signaling by hormones; signaling by hormones; nearby cells nearby cells cytokines; cytokines; or or even secreted by themselves .even secreted by themselves .

Long-range allostery is often a significant component of cell signaling Long-range allostery is often a significant component of cell signaling events. events.

3

CELL SIGNALING

Cell signalingCell signaling is part of a is part of a complex system complex system of communication that governs of communication that governs basic cellular activities and coordinates cell actions.basic cellular activities and coordinates cell actions.

The ability of cells to perceive and correctly respond to their The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, tissue repair, and immunity as microenvironment is the basis of development, tissue repair, and immunity as well as normal tissue homeostasiswell as normal tissue homeostasis

Errors in cellular information processing are responsible for diseases such as Errors in cellular information processing are responsible for diseases such as cancer, autoimmunity, and diabetes. By understanding cell signaling, diseases cancer, autoimmunity, and diabetes. By understanding cell signaling, diseases may be treated effectively and, theoretically, artificial tissues may be created.may be treated effectively and, theoretically, artificial tissues may be created.

4

5

CELL SIGNALING & SIGNAL TRANSDUCTTION

Why do cells communicateWhy do cells communicate How are signals transmitted between cellsHow are signals transmitted between cells How are signals transmitted across cell How are signals transmitted across cell

membranes into cell interior membranes into cell interior How are signals transmitted within a cellHow are signals transmitted within a cell How do signals affect a cell functionHow do signals affect a cell function

6

7

8

SYNTHESIS OF SIGNALLING SYNTHESIS OF SIGNALLING MOLECULES MOLECULES

RELEASE OF SIGNALLING MOLECULES RELEASE OF SIGNALLING MOLECULES

TRANSPORT OF SIGNAL TO TARGET TRANSPORT OF SIGNAL TO TARGET CELLSCELLS

DETECTION & BINDING OF SIGNAL BY SPECIFIC DETECTION & BINDING OF SIGNAL BY SPECIFIC RECEPTOR RECEPTOR

CHANGES DUE TO RECEPTOR-SIGNAL COMPLEXCHANGES DUE TO RECEPTOR-SIGNAL COMPLEX

SIGNAL REMOVAL & SIGNAL REMOVAL & RESPNOSE TERMINATIONRESPNOSE TERMINATION

STEPS IN CELL SIGNALING

9

CLASSIFICATION OF INTERCELLULAR CLASSIFICATION OF INTERCELLULAR COMMUNICATIONCOMMUNICATION

Intercellular signaling is subdivided into the following classifications:Intercellular signaling is subdivided into the following classifications:

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

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

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

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

10

11

12

13

JUXTACRINE SIGNALING

MEMBRANE-ANCHORED LIGANDSMEMBRANE-ANCHORED LIGANDS

NEIGHBOURING NEIGHBOURING CELLSCELLS

14

  e.g.*Notch signalling.e.g.*Notch signalling.

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

Ion Channels

31

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.

32

Cell membrane

33

Membrane transport proteins

34

Only ion channels have an aqueous pore that crosses Only ion channels have an aqueous pore that crosses the membranethe membrane

Ion channels are not pumps

35

Channels are made up of subunits

Ion channels are made from 2-6 similar proteins or homologous Ion channels are made from 2-6 similar proteins or homologous structural units ‐ PORE-FORMING SUBUNITS - they associate structural units ‐ PORE-FORMING SUBUNITS - they associate creating the functional ion channelcreating the functional ion channel

In addition, many channels contain the auxiliary regulatory In addition, many channels contain the auxiliary regulatory subunitssubunits 36

Channels are made up of subunits

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

37

Ion channel types (by gating)

38

Ligand-gated channels

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

Some act in response to a secreted (external) ligand- Some act in response to a secreted (external) ligand- typically a neurotransmitter such astypically a neurotransmitter such as

• Acetylcholine (ACh)Acetylcholine (ACh)• GABAGABA• GlycineGlycine• GlutamateGlutamate

Some act in response to internal ligands such as G-Some act in response to internal ligands such as G-proteins, cGMP and cAMP, and are also regulated by proteins, cGMP and cAMP, and are also regulated by internal metabolites such as phosphoinositides, internal metabolites such as phosphoinositides, arachidonic acid, calcium.arachidonic acid, calcium.

39

Signal-gated channelsAtrial m2 receptor-G protein-Atrial m2 receptor-G protein-coupled Kcoupled K++ channels channels

40

Modifiers of Channel Gating(curare)(curare)

(ACh)(ACh)

(alpha-(alpha-bungarotoxin)bungarotoxin)

Binding of exogenous Binding of exogenous ligands can block gatingligands can block gating

41

Modifiers of Channel Gating

Ion permeation can be Ion permeation can be prevented by pore prevented by pore blockers, e.g. voltage-blockers, e.g. voltage-dependent block of dependent block of NMDARs by MgNMDARs by Mg2+2+

42

Modifiers of Channel Gating

Exogenous modulators can modify the action of endogenous Exogenous modulators can modify the action of endogenous ligandsligands

OpenOpen

ClosedClosed

OpenOpen

ClosedClosed

CurrentCurrent

TimeTime

43

Bu Z, Callaway DJ (2011). "Proteins MOVE! Protein dynamics and long-range Bu Z, Callaway DJ (2011). "Proteins MOVE! Protein dynamics and long-range allostery in cell signaling". allostery in cell signaling". Advances in Protein Chemistry and Structural Advances in Protein Chemistry and Structural BiologyBiology. Advances in Protein Chemistry and Structural Biology . Advances in Protein Chemistry and Structural Biology 8383: 163–221. : 163–221. 

Rang & Dale's PharmacologyRang & Dale's Pharmacology

http://en.wikipedia.org/wiki/Cell_signalinghttp://en.wikipedia.org/wiki/Cell_signaling

http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/C/CellSignaling.htmlhttp://users.rcn.com/jkimball.ma.ultranet/BiologyPages/C/CellSignaling.html

www.authorstream.com/.../shona6685-645587-www.authorstream.com/.../shona6685-645587-pptppt--cellcell--signalingsignaling

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC151254/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC151254/

  Congreve M, Marshall F (March 2010). "The impact of GPCR structures on Congreve M, Marshall F (March 2010). "The impact of GPCR structures on pharmacology and structure-based drug design". pharmacology and structure-based drug design". Br. J. Pharmacol.Br. J. Pharmacol.  159159 (5):  (5): 986–96.doi:10.1111/j.1476-5381.2009.00476x PMC 2839258 PMID19912230986–96.doi:10.1111/j.1476-5381.2009.00476x PMC 2839258 PMID19912230

44

45

46