Cell Signaling (Lecture 2)

1. Cell Signaling (Lecture 2)

2. Types of signaling

3. Autocrine Signaling Can Coordinate Decisions by Groups of Identical Cells • Cells send signals to other cells. • Cells send signals to themselves. • Cell secretes signaling molecules that can bind back to its own receptors. • It is most effective when carried out simultaneously by neighboring cells of the same type. Thus autocrinesignaling is thought to be one possible mechanism underlying the "community effect" observed in early development, where a group of identical cells can respond to a differentiation-inducing signal but a single isolated cell of the same type cannot.

4. (a) (b) (c) (d) (c1) (c2) (c3) (c4) (c5) (c6) (c7) (c8) (c9) (c10) Gap Junctions Allow Signaling Information to Be Shared by Neighboring Cells • Signals are passed to the neighboring cells through gap junctions. • These are specialized cell-cell junctions that can form between closely apposed plasma membranes, directly connecting the cytoplasms of the joined cells via narrow water-filled channels.

5. The channels allow the exchange of small intracellular signaling molecules, such as Ca2+ and cyclic AMP, but not of macromolecules, such as proteins or nucleic acids. • Thus cells connected by gap junctions can communicate with each other directly without having to deal with the barrier presented by the intervening plasma membranes. • gap-junction communication helps adjacent cells of a similar type to coordinate their behavior. • It is not known, however, which particular small molecules are important as carriers of signals through gap junctions; nor has the precise function of gap-junction communication in animal development been defined.

6. Each Cell Is Programmed to Respond to Specific Combinations of Signaling Molecules • Each cell is exposed to many different signals known as combinatorial signaling. • Each cell type displays a set of receptors that enables it to respond to a corresponding set of signaling molecules. • These signaling molecules work in combinations to regulate the behavior of the cell. Many cells require multiple signals ( green arrows) to survive and additional signals ( red arrows) to proliferate; if deprived of all signals, these cells undergo programmed cell death.

7. The same signaling molecule can induce different responses in different target cells

8. Cell response to extracellular signaling • By a receptor that can recognize the signals. • The signal-transduction pathways activated by those receptor upon binding to ligand • The intracellular processes affected by those pathways.

9. Cell Surface Receptors

10. General elements of GPCRs • Most abundant class of receptors • Found in organisms from yeast to man • A receptor with 7 membrane-spanning domains • A coupled trimeric G protein • A membrane bound effector protein • Feedback regulation and desensitization of the signalling pathway • A 2nd messenger present in many GPCRs.

11. Second messengers are molecules that relay signals from receptors on the cell surface to target molecules inside the cell, in the cytoplasm or nucleus. • These components of GPCRs can be mixed and matched to achieve an astonishing number of different pathways • GPCR pathways usually have short term effects in the cells • Allow the cells to respond rapidly to a variety of signals like environmental stimuli (light) or hormonal stimuli (epinephrine)

12. General features • GPCRs have same orientation in the membrane , 7 transmembrane alpha-helical regions, 4 extra cellular segments, 4 cytosolic segments

13. The exterior surface of all GPCR consists of hydrophobic amino acids • Amino acids allow the protein to be stably anchored in the hydrophobic core of the plasma membrane • The amino acids are diverse • Which allow different GPCR to bind very different small molecules • These small molecules can be hydrophilic (epinephrine) and hydrophobic (retinol or odorant)

14. G Protein • Guanine nucleotide-binding proteins, family of proteins involved in transmitting chemical signals originating from outside a cell into the inside of the cell. • G proteins function as molecular switches. Their activity is regulated by their ability to bind to and hydrolyze guanosinetriphosphate (GTP) to guanosinediphosphate  (GDP). • When they bind GTP, they are 'on', and, when they bind GDP, they are 'off'. • G proteins belong to the larger group of enzymes called GTPases. Gβ§

15. Various ligands use G-protein-coupled receptors (GPCRs) to stimulate membrane, cytoplasmic and nuclear targets. GPCRs interact with heterotrimeric G proteins composed of ,  and  subunits that are GDP bound in the resting state. Agonist binding triggers a conformational change in the receptor, which catalyses the dissociation of GDP from the  subunit followed by GTP-binding to G and the dissociation of G from G subunits1. The  subunits of G proteins are divided into four subfamilies: Gs, Gi, Gq and G12, and a single GPCR can couple to either one or more families of G proteins. Each G protein activates several downstream effectors.

16. Activation cycle of a G-protein by a G-protein-coupled receptor receiving a ligand

17. Different G proteins are activated by different GPCRs and inturn regulate different effector proteins. • Effector proteins are in GPCR pathways are either membrane bound ion channels or enzymes that catalyze the formation of the second messengers.

18. GPCR that regulate ion channels • The simplest cellular responses to a signal is the opening or closing of ion channels essential for transmission of nerve impulses • Nerve impulses are essential to the sensory perception of environmental stimuli (light, odor) to transmission of information to and from the brain and to the stimulation of muscle movement • During transmission of nerve impulses, the rapid opening and closing of ion channels causes changes in the membrane potential • Some neurotransmitter receptors are GPCRs whose effector proteins are Na or K channels

19. Neurotramsmitter binding to these receptors causes the associated ion channel to open or close leading to changes in the membrane potential e.g acetyl choline involved in K transport