1. Cell signalling
26 March 2007

2. Overview No cell lives in isolation
In all multicellular organisms, survival depends on an elaborate intercellular communication network that coordinates the growth, differentiation, and metabolism of the multitude of cells in diverse tissues and organs.
Errors in cellular information processing are responsible for diseases such as cancer, autoimmunity, and diabetes. By understanding cell signaling, diseases can be treated effectively and, theoretically, artificial tissues could be built.

3. Cells within small groups often communicate by direct cell-cell contact. Specialized junctions in the plasma membranes of adjacent cells permit them to exchange small molecules and to coordinate metabolic responses; other junctions between adjacent cells determine the shape and rigidity of many tissues.
In addition, the establishment of specific cell-cell interactions between different types of cells is a necessary step in the development of many tissues. In some cases a particular protein on one cell binds to a receptor protein on the surface of an adjacent target cell, triggering its differentiation.

4. Eukaryotic microorganisms
Pheromones coordinate
Sexual mating
Differentiation
Plants, animals
Extracellular signaling controls
Metabolic processes
Growth and differentiation
Protein synthesis

5. In multicellular organisms
Signal molecules produce responses in target cells that have receptors.
In multicellular organisms
Chemicals
Small molecules (aa., lipid derivatives)
Peptides
proteins
Some diffuse and bind to intracellular receptors
Steroids, retinoids, thyroxine

6. Cell signaling pathways

7. Signal transduction
Overall processes converting a signal into cellular responses

8. Cell Signaling Steps involved are: Synthesis
Release from signaling cells
Transport to target cells
Binding to receptor and activation
Signal transduction by activated receptor
Specific changes
Removal of signal (termination)

9. Receptor activation Secreted or membrane bound molecules
Hormones, growth factors, neurotransmitters, pheromones
Changes in the concentration of metabolites
Oxygen or nutrients
Physical stimuli
Light, touch, heat

10. Three types of signaling in animals
Endocrine
hormones
Paracrine
Neurotransmitters
Growth factors
Autocrine
Growth factors (cultured cells, tumor cells)

11. Ligand binding and effector specificity
Each receptor binds only a single ligand or a group of closely related molecules. However, many signaling molecules bind to multiple types of receptors
Acetylcholine binds to different receptors on muscle cells (contraction), heart muscle cells (inhibition of contraction) and pancreas acinar cells (exocytosis of secretory granules), respectively

12. Different receptors of the same class that bind different ligands generate the same cellular response
In liver, ACTH, epinephrine and glucagon bind to different GPCRs; but all three activate the same signaling pathway (cAMP)

13. Intracellular signal transduction
Many receptors transmit signals via second messengers
They rapidly alter the activity of enzymes or non-enzymatic proteins
Ca2+ triggers contraction in muscle cells
Exocytosis of secretory vesicles in endocrine cells
cAMP generates different metabolic changes in different type of cells

14. Regulation of signaling
External signal decreases
Degradation of second mesenger
Desensitization to prolonged signaling
Receptor endocytosis
Modulation of receptor activity
Phosphorylation
Binding to other proteins

15. Receptors

16. Hormones Can Be Classified Based on Their Solubility and Receptor Location
Most hormones fall into three broad categories:
(1) small lipophilic molecules that diffuse across the plasma membrane and interact with intracellular receptors;
(2) hydrophilic or (3) lipophilic molecules that bind to cell-surface receptors.
Recently, nitric oxide, a gas, has been shown to be a key regulator controlling many cellular responses

17. Classification of receptors
Intracellular receptors (for lipid soluble messengers)
function in the nucleus as transcription factors to alter the rate of transcription of particular genes.
Plasma membrane receptors (for lipid insoluble messengers)
Receptors function as ion channels
receptors function as enzymes or are closely associated with cytoplasmic enzymes
receptors that activate G proteins which in turn act upon effector proteins, either ion channels or enzymes, in the plasma membrane.

18. Hormones bind to intracellular receptors and to cell-surface receptors

19. Nitric oxide

20. Intracellular Receptors
Extracellular signal molecules are small, lipid-soluble hormones such as steroid hormones, retinoids, thyroid hormones, Vitamin D. (Made from cholesterol)
These hormones diffuse through plasma and nuclear membranes and interact directly with the transcription factors they control.

22. Sequence similarities and three functional regions
N-terminal region of variable length ( aa); in some receptors portions of this region act as activation domain
At the center, DNA binding domain, made of a repeat of C4-zinc finger motif
Near the C-terminal end, an hormone binding domain, which may act as an activation or repression domain.

23. The intracellular receptor superfamily.

24. Nuclear receptor response elements
Some characteristic sites of DNA are called response elements and can bind several nuclear receptors.
These repeat regions are arranged either as an invert repeat, or direct repeat.
Inverted repeat: glucocorticoid response element; estrogen response element
Repeats are separated by any three bases, implicating symmetrical binding of the receptor homodimer to DNA

26. Receptors for vitaminD, retinoic acid and thyroid hormone bind to direct repeats as heterodimers,
Second component of the heterdimer is RXR monomer (i.e, RXR-RAR; RXR-VDR)
The specifity of the binding is determined by the spacing between repeats.

27. Regulation of transcription activity
Regulatory mechanisms differ for hetero-dimeric and homodimeric receptors
Heterodimeric receptors are exclusively nuclear; without ligand, they repress transcription by binding to their cognate sites in DNA
They do so by histone deacetylation

28. Homodimeric receptors are cytoplasmic in the absence of ligands.
Hormone binding leads to nuclear translocation of receptors
Absence of hormone causes the aggregation of receptor as a complex with inhibitor proteins, such as Hsp90

30. Early primary response (A) and delayed secondary response (B) that result from the activation of an intracellular receptor protein.