Cell Signaling (part 1)

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1 15 Cell Signaling (part 1)

2 Introduction Bacteria and unicellular eukaryotes respond to environmental signals and to signaling molecules secreted by other cells for mating and other communication. In multicellular organisms, cell-cell communication is highly sophisticated. Each cell must be carefully regulated to meet the needs of the organism.

3 Introduction Communication is accomplished by signaling molecules from one cell that bind to receptors on other cells. This initiates a series of reactions that regulate virtually all aspects of cell behavior.

4 Introduction Many cancers arise from problems in the signaling pathways that control normal cell proliferation and survival. Many of our current insights into cell signaling mechanisms have come from the study of cancer cells.

5 Signaling Molecules and Their Receptors Signaling molecules differ in modes of action: Some cross the plasma membrane and bind to intracellular receptors; others bind to receptors on the cell surface.

6 Signaling Molecules and Their Receptors Modes of cell signaling include: Direct cell-cell signaling direct interaction of a cell with its neighbor, (e.g., via integrins and cadherins). Signaling by secreted molecules - three categories are based on the distance over which signals are transmitted.

7 Figure 15.1 Modes of cell cell signaling

8 Signaling Molecules and Their Receptors Small hydrophobic molecules can diffuse across the plasma membrane. Examples: Steroid hormones, thyroid hormone, vitamin D 3, and retinoic acid.

9 Signaling Molecules and Their Receptors Receptors for these molecules are members of the nuclear receptor superfamily. They are transcription factors that regulate target gene expression.

10 Signaling Molecules and Their Receptors Ligand binding has different effects on different receptors. Some nuclear receptors are inactive in the absence of hormone: Glucocorticoid receptor is bound to Hsp90 chaperones in the absence of hormone. Glucocorticoid binding displaces Hsp90 and leads to binding of regulatory DNA sequences.

11 Figure 15.3 Glucocorticoid action

12 Signaling Molecules and Their Receptors Hormone binding can alter the activity of a receptor: In the absence of hormone, thyroid hormone receptor is associated with a corepressor complex and represses transcription of target genes. Hormone binding results in activation of transcription.

13 Figure 15.4 Gene regulation by the thyroid hormone receptor

14 Signaling Molecules and Their Receptors Nitric oxide (NO) is a paracrine signaling molecule in the nervous, immune, and circulatory systems. It can cross the plasma membrane and alter the activity of enzymes. NO is synthesized from arginine. Its action is restricted to local effects, because it is extremely unstable, with a half-life of only a few seconds.

15 Figure 15.5 Synthesis of nitric oxide

16 Signaling Molecules and Their Receptors The main target of NO is guanylyl cyclase. NO binding stimulates synthesis of the cyclic GMP. NO can signal dilation of blood vessels: Neurotransmitters act on endothelial cells to stimulate NO synthesis. NO diffuses to smooth muscle cells and stimulates cgmp production. cgmp induces muscle cell relaxation and blood vessel dilation.

17 Signaling Molecules and Their Receptors

18 Signaling Molecules and Their Receptors Carbon monoxide (CO), also functions as a signaling molecule in the nervous system. It is related to NO and acts similarly as a neurotransmitter and mediator of blood vessel dilation.

19 Signaling Molecules and Their Receptors Neurotransmitters carry signals between neurons or from neurons to other target cells. Neurotransmitters are released when an action potential arrives at the end of a neuron. The neurotransmitters then diffuse across the synaptic cleft and bind to receptors on the target cell surface.

20 Figure 15.6 Structure of representative neurotransmitters

21 Signaling Molecules and Their Receptors Because neurotransmitters are hydrophilic; they can t cross plasma membranes and must bind to cell surface receptors. Many neurotransmitter receptors are ligand-gated ion channels. Neurotransmitter binding opens the channels. Other neurotransmitter receptors are coupled to G proteins - a major group of signaling molecules that link cell surface receptors to intracellular responses.

22 Signaling Molecules and Their Receptors Peptide signaling molecules include peptide hormones, neuropeptides, and polypeptide growth factors. Peptide hormones include insulin, glucagon, and pituitary gland hormones.

23 Table 15.1 Representative peptide hormones, neuropeptides, and polypeptide growth factors EGF

24 Signaling Molecules and Their Receptors Cytokines regulate development and differentiation of blood cells and activities of lymphocytes during the immune response. Membrane-anchored growth factors remain associated with the plasma membrane and function as signaling molecules in direct cell-cell interactions.

25 Signaling Molecules and Their Receptors Eicosanoids: lipid signaling molecules that include prostaglandins, prostacyclin, thromboxanes, and leukotrienes. They break down rapidly, acting in autocrine or paracrine pathways. Eicosanoids are synthesized from arachidonic acid, which is formed from phospholipids. Arachidonic acid is converted to prostaglandin H 2, catalyzed by cyclooxygenase. This enzyme is the target of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs).

26 Figure 15.8 Synthesis and structure of eicosanoids

27 Signaling Molecules and Their Receptors Inhibiting synthesis of the prostaglandins reduces inflammation and pain. By inhibiting synthesis of thromboxane, aspirin reduces platelet aggregation and blood clotting; thus, small daily doses of aspirin are often prescribed for prevention of strokes. Aspirin and NSAIDs have also been found to reduce the frequency of colon cancer, apparently by inhibiting synthesis of prostaglandins that stimulate cell proliferation.

28 Signaling Molecules and Their Receptors There are two forms of cyclooxygenase: COX-1 results in normal production of prostaglandins. COX-2 results in increased prostaglandin production associated with inflammation and disease. Some drugs selectively inhibit COX-2.

29 Functions of Cell Surface Receptors Most ligands responsible for cell-cell signaling bind to surface receptors on their target cells. This initiates a chain of intracellular reactions, ultimately reaching the nucleus and resulting in programmed changes in gene expression.

30 Functions of Cell Surface Receptors G protein-coupled receptors are the largest family of cell surface receptors. Signals are transmitted via guanine nucleotidebinding proteins (G proteins). The receptors have seven membrane-spanning α helices.

31 Functions of Cell Surface Receptors Binding of a ligand induces a conformational change that allows the cytosolic domain to activate a G protein on the inner face of the plasma membrane. The activated G protein then dissociates from the receptor and carries the signal to an intracellular target.

32 Functions of Cell Surface Receptors G proteins have three subunits designated α, β, and γ. The α subunit binds guanine nucleotides, which regulate G protein activity. In the inactive state, α is bound to GDP in a complex with β and γ. Hormone binding to the receptor causes exchange of GTP for GDP. The α and βγ complex then dissociate from the receptor and interact with their targets.

33 Functions of Cell Surface Receptors A G protein is an intermediary in adenylyl cyclase activation, which synthesizes camp.

34 Figure Regulation of G proteins

35 Functions of Cell Surface Receptors In addition to enzyme regulation, G proteins can also regulate ion channels. Example: action of the neurotransmitter acetylcholine on heart muscle.

36 Functions of Cell Surface Receptors Heart muscle cells have a different acetylcholine receptor than nerve and skeletal muscle cells, which is G protein coupled. The α subunit of this G protein (G i ) inhibits adenylyl cyclase. The G i βγ subunits open K + channels in the plasma membrane, which slows heart muscle contraction.

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