Molecular interaction, Regulation and Signalling receptors and vesicles
- 1. BIO-MEMBRANE, BIO-ENERGY CELL TRAFFICKING TOPIC: MOLECULAR INTERACTION, REGULATION & SIGNALLING RECEPTORS & VESICLES ANANTHAKUMAR.T BMS14312
- 2. Overview of Extracellular Signaling Communication by extracellular signals usually involves six steps: 1. Synthesis 2. Release of the signaling molecule by the signaling cell; 3. Transport of the signal to the target cell; 4. Detection of the signal by a specific receptor protein; 5. A change in cellular metabolism, function, or development triggered by the receptor-signal complex; 6. Removal of the signal, which often terminates the cellular response.
- 3. Signaling Molecules Operate over Various Distances in Animals • In animals, signaling by extracellular, secreted molecules can be classified into three types ; 1. Endocrine, 2. Paracrine, 3. Autocrine • Based on the distance over which the signal acts. • In addition, certain membrane-bound proteins on one cell can directly signal an adjacent cell
- 4. ENDOCRINE SIGNALING • Signaling molecules, called hormones, act on target cells distant from their site of synthesis by cells of endocrine organs. • In animals, an endocrine hormone usually is carried by the blood from its site of release to its target.
- 5. PARACRINE SIGNALING The signaling molecules released by a cell only affect target cells in close proximity to it. The conduction of an electric impulse from one nerve cell to another or from a nerve cell to a muscle cell (inducing or inhibiting muscle contraction) occurs via paracrine signaling.
- 6. AUTOCRINE SIGNALING Cells respond to substances that they themselves release. Many growth factors act in this fashion, and cultured cells often secrete growth factors that stimulate their own growth and proliferation. This type of signaling is particularly common in tumor cells, many of which overproduce and release growth factors that stimulate inappropriate, unregulated proliferation of themselves as well as adjacent non tumor cells; this process may lead to formation of tumor mass.
- 7. Some compounds can act in two or even three types of cell-to-cell signaling. Certain small amino acid derivatives, such as epinephrine, function both as neurotransmitters (paracrine signaling) and as systemic hormones (endocrine signaling).
- 8. SIGNALING BY PLASMA MEMBRANE ATTACHED PROTIENS Some protein hormones, such as epidermal growth factor (EGF), are synthesized as the exoplasmic part of a plasma- membrane protein; membrane-bound EGF can bind to and signal an adjacent cell by direct contact.
- 9. RECEPTORS • Most receptors are on cell surface --- Water soluble signaling molecules cannot cross membrane lipid bilayer but are capable of binding to specific receptors embedded in the plasma membrane. • Receptors have an a) Extracellular domain that binds signaling molecule b) hydrophobic transmembrane domain and c) intracellular domain. • On binding a ligand, there induces a conformational change in the receptor, in particular of the intracellular region which in turn activates a relay of intracellular signaling molecules… thus bringing about appropriate cellular responses such as altered metabolism, altered cytoskeleton or altered gene expression or cell division.
- 10. PROPERTIES OF RECEPTORS • Specificity – Signaling molecule or ligand recognizes and binds to its specific receptor just as an enzyme binds to its substrate and this binding is independent from competition from other signaling molecules • High Affinity – Receptors usually bind to their signaling molecules with high affinity as determined by their affinity constants Ki and also the interaction shows low dissociation constants Kd indicating high affinity binding.
- 11. • Saturation Kinetics – Number of receptors on the surface of a cell is limited and the number varies from less than a dozen to several thousand depending on the receptor type. Increasing the signal ligand concentration would eventually result in receptor saturation meaning all sites being occupied by ligands. • Reversibility – Normally the binding of a signaling ligand to a receptor is reversible and this is necessary property to prevent permanent activation of the receptor • Physiological Response – Ligand receptor binding triggers a physiological response characteristic for its interaction such as binding of insulin to insulin receptor (INSR) stimulates glucose transport into target cells. The magnitude of the response is directly related to the number of receptors to which the ligands bind.
- 12. Cell-Surface Receptors Belong to Four Major Classes • G protein – coupled receptors : Ligand binding activates a G protein, which in turn activates or inhibits an enzyme that generates a specific second messenger or modulates an ion channel, causing a change in membrane potential. • The receptors for epinephrine, serotonin, and glucagon are examples.
- 13. • Ion-channel receptors : Ligand binding changes the conformation of the receptor so that specific ions flow through it; the resultant ion movements alter the electric potential across the cell membrane. The acetylcholine receptor at the nerve-muscle junction is an example.
- 14. Tyrosine kinase – linked receptors: These receptors lack intrinsic catalytic activity, but ligand binding stimulates formation of a dimeric receptor, which then interacts with and activates one or more cytosolic protein-tyrosine kinases. The receptors for many cytokines, the interferons, and human growth factor are of this type. These tyrosine kinase – linked receptors sometimes are referred to as the cytokine-receptor superfamily.
- 16. Receptors with intrinsic enzymatic activity : Several types of receptors have intrinsic catalytic activity, which is activated by binding of ligand. For instance, some activated receptors catalyze conversion of GTP to cGMP; others act as protein phosphatases, removing phosphate groups from phosphotyrosine residues in substrate proteins, thereby modifying their activity. The receptors for insulin and many growth factors are ligand-triggered protein kinases; in most cases, the ligand binds as a dimer, leading to dimerization of the receptor and activation of its kinase activity. These receptors — often referred to as receptor serine/threonine kinases or receptor tyrosine kinases — auto phosphorylate residues in their own cytosolic domain and also can phosphorylate various substrate proteins.
- 18. SIGNAL TRANSDUCTION MECHANISMS Signaling information has to be transmitted from the receptor in the plasma membrane across the cytoplasam to the nucleus ( If gene transcription is the response required), the cytoskeleton ( If cell movement or another change to cell morphology is the response) or various other subcellular compartments. These responses are expected to occur within a suitable time frame so as to have some synchronicity with regarding transmission or signal and cellular response. In a typical model of signaling a chain of intracellular mediators successively activates the next target in the chain, as in a branching network of activation, diversification and modulation of response. Thus the branched molecular network of activation ( or deactivation ) of signaling molecules linking receptor activation to the intracellular targets is referred to as a signal transduction pathway ( or cascade ).
- 19. SECOND MESSENGERS Intracellular signaling molecules have properties that allow control of the speed, duration and target of the signal and be categorized accordingly. Broadly they can be divided into 2 groups on the basis of their molecular characteristics, Second Messengers and Signaling Proteins. 1. Second Messengers are small readily diffusible intracellular mediators regulating the activity of other target signaling molecules. The calcium ions Ca2+ is a classic example of a second messenger being released in large quantities in response to a signal (amplifying the signal ) and diffusing rapidly through the cytosol and help in broadcasting the signal quickly to several distant parts of the cell. Eg. Ca2+ ions mediate and coordinate contraction of skeletal muscle cells. Thus if rapid response is needed second messengers will definitely be present in the signalling pathway.
- 20. 2. Second messengers are water soluble such as cyclic nucleotides cAMP and cGMP and act similarly to Ca2+ ions by diffusing through the cytosol, whereas second messengers such as diacylglycerol ( DAG ) are lipid soluble and diffuse along the inside of the plasma membrane where other key signaling proteins are anchored. 3. In the G protien coupled receptor (GPCR) system the effector enzyme adenylyl cyclase synthesizes the second messenger cAMP from ATP and guanylyl cyclase synthesizes cGMP from GTP. 4. Resultant rise in cAMP and cGMP affects various cell types in different ways. Diverse effects of cAMP are mediated by enzymes called protein kinases A (PKAs) and does not function in signalling pathways mediated by receptor tyrosine kinases (RTKs).
- 21. Contraction of Skeletal Muscle Cells - Mechanism A. Acetylcholine (ACH) is released from the neuronal terminal and binds to ACH – gated Na+ channels on the surface of the muscle cell. B. The receptors are ion channels and hence promote local depolarization ( increase in membrane potential caused by entry of sodium ions ) C. Depolarization is propagated in the muscle cell by voltage gated Na+ ion channels which allow further Na+ ion entry. D. Increased general deploarization triggers rapid release of Ca2+ ions into sarcoplasam ( muscle cytoplasam ) through voltage-gated Ca2+ from stores in sarcoplasmic reticulum; the Ca2+ ions spread throughout the muscle cell. E. Rapid increase of Ca2+ ions in sarcoplasam enables rapid and synchronous contraction of muscles filaments and Ca2+ ions achieves this by binding to inhibitory protein complex of tropomyosin and troponin which under resting conditions prevent actin and myosin filaments from interacting.
- 22. • Calcium ions help to synchronize rapid contraction of skeletal muscle cells
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