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Membranes: Keeping things where they belong • Separate functional and anatomic fluid compartments in the body. • Regulate the transport of materials between compartments Connections between plasma membranes • Extracellular matrix: primarily secreted by fibroblasts. – Collagen: forms cable-like fibers that provide tensile strength; especially important in skin and blood vessels. *Scurvy: in vitamin C deficiency these fibers are not properly formed. – Elastin: rubber-like protein where elasticity (ability to return to prestress orientation) is important; especially important in arteries and lungs. – Fibronectin: promotes cell-cell adhesion and can hold cells in position. Adjacent intestinal epithelial cells Tight Junctions Intracellular Extracellular Transmembrane Proteins Connections between plasma membranes • Extracellular matrix • Tight junctions: zona occludens – Impermeable (usually) connectio – ns between cells. – Cell membranes are attached to each other by strands of junctional proteins. Extracellular Intracellular keratin filaments Intracellular Spot Desmosome Thickened “plaque” area Intercellular filaments (commonly glycoproteins) Connections between plasma membranes • Extracellular matrix • Tight junctions: zona occludens • Spot desmosomes: macula adherens (~20 nm) – anchor cells together with some space to accommodate movement/stretching. • Cytoplasmic plaque • Intracellular intermediate filaments through cells connecting various plaques • Intercellular glycoprotiens connect the cells Extracellular Intracellular Passage of ions And small molecules 1.5 nm Large molecules blocked Gap Junctions Connexons Connections between plasma membranes • Extracellular matrix • Tight junctions: Tight junctions: zona occludens • Spot desmosomes: macula adherens • Gap Junctions: no fancy latin name; 2-4 nm – Communication between cells through connexons – Permit passage of small ions and particles between cell's cytoplasm Membrane Transport • Passive: movement of material without the expenditure of energy. – Simple Diffusion • particles in random motion display net movement relative to two conditions – Chemical gradient: material moves "down" it's concentration gradient. Membrane Transport • Passive: movement of material without the expenditure of energy. – Simple Diffusion • particles in random motion display net movement relative to two conditions – Chemical gradient: material moves "down" it's concentration gradient. * Osmosis: the movement of water "down" it's concentration gradient. *Osmotic pressure: a "negative" effective pressure that acts to "pull" water Semi-permeable X mmHg X mmHg Membrane Transport Passive: movement of material without the expenditure of energy. • Simple Diffusion – particles in random motion display net movement relative to two driving force conditions • Chemical gradient: material moves "down" it's concentration gradient. • Ionic charge: electrical attaction/repulsion – Other factors influencing volume-rate diffusion • Permeability of the membrane to the substance – Lipid-soluble-passes through – Water-soluble - generally require selective channels or pores • Molecular weight of the substance • Surface area • Distance (thickness of the membrane) • Facilitated (carrier-mediated) diffusion - the diffusion of the material occurs via specialized protein "carriers" Membrane Transport Passive: movement of material without the expenditure of energy. • Simple diffusion • Facilitated (carrier-mediated) diffusion - the diffusion of the material occurs via specialized protein "carriers" – particles in random motion display net movement relative to their electrochemical gradient – Display unique characteristics • Specificity: only one molecule (or class of molecules) transported • Saturation: The rate of transport of molecules is limited to the number of carriers. There are only so many lifeboats on the Titanic • Competition: When the carrier can transport multiple forms of a molecule (or drugs that closely resemble the molecule), the multiple forms compete for the limited number of carriers. If a ferry has 100 seats, and 70 are occupied by women, ony 30 men are getting across. Membrane Transport Passive: movement of material without the expenditure of energy. • Simple diffusion • Facilitated (carrier-mediated) diffusion Active Transport: requiring the expenditure of energy • Primary: Energy used directly in transport of the molecule(s) Membrane Transport Passive: movement of material without the expenditure of energy. • Simple diffusion • Facilitated (carrier-mediated) diffusion Active Transport: requiring the expenditure of energy • Primary: Energy used directly in transport of the molecule(s) – Typical series of events • ATP is used to phosphorylate the carrier – carrier becomes exposed to the side with low concentration of the molecule to be transported – Increased affinity for the transported molecule • Binding of the molecule usually causes conformational (structrural) change – Molecule is exposed to high concentration side – Carrier is dephosphorylated – Affinity for the molecule decreases, and the molecule is released – Simple design: one molecule (or class), one direction – Complex designs: multiple molecules; mutiple directions Membrane Transport Passive: movement of material without the expenditure of energy. • Simple diffusion • Facilitated (carrier-mediated) diffusion Active Transport: requiring the expenditure of energy • Primary: Energy used directly in transport of the molecule(s) – Typical series of events • ATP is used to phosphorylate the carrier – carrier becomes exposed to the side with low concentration of the molecule to be transported – Increased affinity for the transported molecule • Binding of the molecule usually causes conformational (structrural) change – Molecule is exposed to high concentration side – Carrier is dephosphorylated – Affinity for the molecule decreases, and the molecule is released – Simple design: one molecule (or class), one direction – Complex designs: multiple molecules; mutiple directions • Counter-transport: multiple molecules, opposite direction (3Na+/2K+) • Co-transport: multiple molecules, same direction (not common) • Secondary: Potential energy of another molecule used (commonly Na+) Membrane Transport Passive: movement of material without the expenditure of energy. • Simple diffusion • Facilitated (carrier-mediated) diffusion Active Transport: requiring the expenditure of energy • Primary: Energy used directly in transport of the molecule(s) • Secondary: Potential energy of another molecule used (commonly Na+) • Counter-transport: multiple molecules, opposite direction (Na+/H+) • Co-transport: multiple molecules, same direction (Na+/Glucose) • Vesicular – Clathrin "coated pit" pathway • Endocytosis • Exocytosis – Potocytosis- the caveolae pathway • Specialized caveolin-rich "pit" in membranes with cholesterol-stabilized constituents • Sometimes maintains "tether" connection to the membrane • Involved in many receptor-mediated communication processes Membrane Potential Membrane Potential An electrical potential caused by unbalanced distribution (in/out) of cations and anions. – All cells – Can primarily be attriubuted to • Na/K exchange pump: pumps more cations out than anions in. • Differences in permeability to Na and K: cell is much more permeable to K than to Na; the concentration gradient (K our) is balanced by the attraction of anions inside. • Membrane impermeable anionic proteins Membrane Potential An electrical potential caused by unbalanced distribution (in/out) of cations and anions. – All cells – Can primarily be attriubuted to • Na/K exchange pump: pumps more cations out than anions in. • Differences in permeability to Na and K: cell is much more permeable to K than to Na; the concentration gradient (K our) is balanced by the attraction of anions inside. • Membrane impermeable anionic proteins – Uses of the membrane potential: • Communication via electrical transmission - primarily nerve and muscle • Secondary energy source for transport Cellular Communicaton Autocrine Endocrine Neural Communications Ligand-receptor mediation • Gated Channels- receptor activation "opens" channels for ions to move – Electrical potential transmission – Ions controlling secretion (eg: Ca) • Second-messenger systems – G-protein coupled E1 E2 GDP GTP E1 E2 GDP GTP Communications Ligand-receptor mediation • Gated Channels- receptor activation "opens" channels for ions to move – Electrical potential transmission – Ions controlling secretion (eg: Ca) • Second-messenger systems – G-protein coupled • General Scheme: – Inactive: alpha,beta, and gamma subunits together; GDP bound – Binding of GTP to alpha subunit activates; alpha +/- beta:gamma subunits alter activity of an effector molecule (kinase or phsphatase) – Hydrolysis of GTP to GDP inactivates the G protein subunits *Inactivation of G-protein does not necessarily inactivate effector. Thus, the chemical half-life and biological half-life are often very different. *The same second messenger can cause different responses in different cells epinephrine Adenylyl Cyclase Beta-adrenergic receptor AC adenosine GTP ATP cAMP GDP ADP PKA Phosphorylate specific protein Communications Ligand-receptor mediation • Gated Channels- receptor activation "opens" channels for ions to move – Electrical potential transmission – Ions controlling secretion (eg: Ca) • Second-messenger systems – G-protein coupled • General Scheme • Examples: – Adenylyl Cyclase » Gs-alpha stimulates AC to enzymatically form cyclic-AMP from ATP » cAMP activates protein kinase A, which in turn, phosphosylates a target protein » Degradation of cAMP to AMP may overwhelm th ability to re-phosphorylate; adenosine is produced » Adenosine activates an inhibitory G-protein which inhibits AC- negative feedback control PIP2 PLC PKC DAG IP3 Signals the release of Calcium from ER Ca++ Phosphorylate specific protein Communications Ligand-receptor mediation • Gated Channels- receptor activation "opens" channels for ions to move – Electrical potential transmission – Ions controlling secretion (eg: Ca) • Second-messenger systems – G-protein coupled • General Scheme • Examples: – Adenylyl Cyclase » Gs-alpha stimulates AC to enzymatically form cyclic-AMP from ATP » cAMP activates protein kinase A, which in turn, phosphosylates a target protein » Degradation of cAMP to AMP may overwhelm th ability to re-phosphorylate; adenosine is produced » Adenosine activates an inhibitory G-protein which inhibits AC- negative feedback control – Phosphatidylinositol isphosphate (PIP2) » Gs-alpha activates phospholipase C (PLC) » PLC cleaves PIP2 inot inositol-triphosphate (IP3) and diacylglycerol (DAG) » IP3 causes the release of intracelular Ca Calmodulin is activated by binding with Ca Activated calmodulin then activates or inhibits other proteins » DAG acts as a separate second messenger (often protein kinase C [PKC]). Apoptosis Direct hydrolysis Activation of other systems OH - Caspases ? Cell Death End of the road • Necrosis: usually associated with ischemia or abrupt damage: – Disorganized; loss of membrane integrity – Cell swelling and rupture; lysosomal enzymes released – Inflammatory response • Apoptosis: ordered death – Activation of Caspases by • mitochondrial cytochrome release • second messenger system • transcriptional regulation – Caspases activate other caspases and addtional hydrolytic enzyme systems; cleave cellular components into organized fragments for disposal