Compendium of physiology  What is physiology?  Physiological genomics is the link between the organ and the gene  Cells live in a highly protected milieu intérieur  Homeostatic mechanisms — operating through sophisticated feedback control mechanisms — are responsible for maintaining the constancy of the milieu intérieur  Homeostasis  Negative feedback mechanisms  The surface of the cell is defined by a membrane  Impermeable – large molecules  Selectively permeable – ions and metabolites  Active transport accumulation against concentration gradient  The cell membrane is composed primarily of phospholipids Types of membrane proteins mediating translocation across cell membrane : passive transport across ion channels (a) or carriers (b) are driven by a chemical gradient. Ion channels are classified into three groups according to their mechanism of opening: voltage-gated ion channels open after membrane depolarization, ligand-gated ion channels following a ligand binding, whereas mechanosensitive channels open upon mechanic stimulation. (c) Active transport by transporters allow a transport against a chemical gradient thanks to the consumption of energy, e.g. by ATP hydrolysis.  Phospholipids form complex structures in aqueous solution  The diffusion of individual lipids within a leaflet of a bilayer is determined by the chemical makeup of its constituents  phosphatidylinositols  phosphatidylserines  phosphatidylcholines  sphingolipids (derivatives of sphingosine),  sphingomyelins  glycosphingolipids such as the galactocerebrosides  Gangliosides  Cholesterol  Ions (-)  Large water-soluble molecules (-)  Uncharged polar molecules (O2, CO2, NH3, water) (+)  Peripherally associated membrane proteins  Integral membrane proteins  Transmembrane proteins  Glycophospholipidlinked proteins  Some membrane proteins are mobile in the plane of the bilayer  Integral membrane proteins can serve as receptors  Integral membrane proteins can serve as adhesion molecules  Integral membrane proteins can carry out the transmembrane movement of water-soluble substances  Integral membrane proteins can participate in intracellular signaling  Peripheral membrane proteins participate in intracellular signaling and can form a submembranous cytoskeleton  The cell is composed of discrete organelles that subserve distinct functions  The nucleus stores, replicates, and reads the cell’s genetic information  Lysosomes digest material that is derived from the interior and exterior of the cell  The mitochondrion is the site of oxidative energy production  The cytoplasm is not amorphous but is organized by the cytoskeleton  Intermediate filaments provide cells with structural support  Microtubules provide structural support and provide the basis for several types of subcellular motility  Thin fi laments (actin) and thick filaments (myosin) are present in almost every cell type  Secretory and membrane proteins are synthesized in association with the rough endoplasmic reticulum  Simultaneous protein synthesis and translocation through the rough endoplasmic reticulum membrane requires signal recognition and protein translocation machinery  Newly synthesized secretory and membrane proteins undergo posttranslational modification and folding in the lumen of the rough endoplasmic reticulum  Secretory and membrane proteins follow the secretory pathway through the cell  Carrier vesicles control the traffic between the organelles of the secretory pathway  Specialized protein complexes, such as clathrin and coatamers, mediate the formation and fusion of vesicles in the secretory pathway  Cells internalize extracellular material through the process of endocytosis  Cells can communicate with one another by chemical signals  Hormones and chemical signals  Endocrine, paracrine, autocrine  Soluble chemical signals interact with target cells by binding to surface or intracellular receptors  Recognition  Transduction  Transmission  Modulation of the effector (phosphatases/kinases)  Response  Termination  Gap junctions  Adhering and Tight Junctions  Membrane-Associated Ligands  Ligand-gated ion channels transduce a chemical signal into an electrical signal  Ionotropic receptors  ACh, serotonin, γaminobutyric acid (GABA), and glycine  IP3 receptor  ryanodine receptor  G proteins are heterotrimers that exist in many combinations of different a, b, and g subunits  G protein activation follows a cycle  Activated α subunits couple to a variety of downstream effectors, including enzymes, ion channels, and membrane trafficking machinery  AA signaling pathways. In the direct pathway, an agonist binds to a receptor that activates PLA2, which releases AA from a membrane phospholipid (see Fig. 3-10). In one of three indirect pathways, an agonist binds to a different receptor that activates PLC and thereby leads to the formation of DAG and IP3, as in Figure 3-8; DAG lipase then releases the AA from DAG. In a second indirect pathway, the IP3 releases Ca2+ from internal stores, which leads to the activation of PLA2 (see the direct pathway). In a third indirect pathway (not shown), mitogen-activated protein kinase stimulates PLA2. Regardless of its source, the AA may follow any of three pathways to form a wide array of eicosanoids. The cyclooxygenase pathway produces thromboxanes, prostacyclins, and prostaglandins. The 5-lipoxygenase pathway produces 5-HETE and the leukotrienes. The epoxygenase pathway leads to the production of other HETEs and EETs. ASA, acetylsalicylic acid; EET, cisepoxyeicosatrienoic acid; ER, endoplasmic reticulum; HETE, hydroxyeicosatetraenoic acid; HPETE, hydroperoxyeicosatetraenoic acid; MAG, monoacylglycerol.  Receptor guanylyl cyclases  Receptor serine/threonine kinases  Receptor tyrosine kinases  Tyrosine kinase–associated receptors  Receptor tyrosine phosphatases  The receptor guanylyl cyclase transduces the activity of atrial natriuretic peptide, whereas a soluble guanylyl cyclase transduces the activity of nitric oxide  Receptor tyrosine kinases produce phosphotyrosine motifs recognized by SH domains of downstream effectors  Tyrosine kinase–associated receptors activate loosely associated tyrosine kinases such as Src and JAK  Receptor tyrosine phosphatases are required for lymphocyte activation  Steroid and thyroid hormones enter the cell and bind to members of the nuclear receptor superfamily in the cytoplasm or nucleus  Total body water is the sum of the intracellular and extracellular fluid volumes Intracellular fluid is rich in K+, whereas the extracellular fluid is rich in Na+ and Cl  Osmolality  Bulk elektronegativity  the number of positive charges in the overall solution must be the same as the number of negative charges  In passive, noncoupled transport across a permeable membrane, a solute moves down its electrochemical gradient  At equilibrium, the chemical and electrical potential energy differences across the membrane are equal but opposite  In simple diffusion, the fl ux of an uncharged substance through membrane lipid is directly proportional to its concentration difference  Some substances cross the membrane passively through intrinsic membrane proteins that can form  pores  channels  carriers  Water-fi lled pores can allow molecules, some as large as 45 kDa, to cross membranes passively  Gated channels, which alternately open and close, allow ions to cross the membrane passively  Na+ channels - because the electrochemical driving force for Na+ (Vm − ENa) is always strongly negative (Table 5-3), a large, inwardly directed net driving force or gradient favors the passive movement of Na+ into virtually every cell of the body  K+ channels - the electrochemical driving force for K+ (Vm − EK) is usually fairly close to zero or somewhat positive (Table 5-3), so K+ is either at equilibrium or tends to move out of the cell  Ca2+ channels - the electrochemical driving force for Ca2+ (Vm − ECa) is always strongly negative (Table 5-3), so Ca2+ tends to move into the cell  Anion channels - most cells contain one or more types of anion-selective channels through which the passive, noncoupled transport of Cl− —and, to a lesser extent, HCO3 − —can take place. The electrochemical driving force for Cl− (Vm − ECl) in most cells is modestly negative (Table 5-3), so Cl− tends to move out of these cells  The Na-K pump, the most important primary active transporter in animal cells, uses the energy of ATP to extrude Na+ and to take up K+ Besides the Na-K pump, other P-type ATPases include the HK and Ca2+ pumps  Na+ /glucose cotransporter (SGLT)  Na+-Driven Cotransporters for Organic Solutes  Na/HCO3 Cotransporters  Na+-Driven Cotransporters for Other Inorganic Anions  Na/K/Cl Cotransporter  Na/Cl Cotransporter  K/Cl Cotransporter  H+-Driven Cotransporters  Na-Ca Exchanger  Na-H Exchanger  Na+-Driven Cl-HCO3 Exchanger  Cl-HCO3 Exchanger  Other Anion Exchangers  The Na-K pump keeps [Na+ ] inside the cell low and [K+ ] high  The Ca2+ pump and the Na-Ca exchanger keep intracellular [Ca2+ ] four orders of magnitude lower than extracellular [Ca2+ ]  Ca2+ Pumps (SERCA) in Organelle Membranes  Ca2+ Pump (PMCA) on the Plasma Membrane  Na-Ca Exchanger (NCX) on the Plasma Membrane  In most cells, [Cl- ] is modestly above equilibrium because Cl- uptake by the Cl-HCO3 exchanger and Na/K/Cl cotransporter balances passive Cl- efflux through channels  The Na-H exchanger and Na+ -driven HCO3 - transporters keep the intracellular pH and [HCO3 - ] above their equilibrium values  Water transport is driven by osmotic and hydrostatic pressure differences across membranes  The Na-K pump maintains cell volume by doing osmotic work that counteracts the passive Donnan forces  Cell volume changes trigger rapid changes in ion channels or transporters, returning volume toward normal  Water Exchange Across Cell Membranes  Adding isotonic saline, pure water, or pure NaCl to the ECF will increase ECF volume but will have divergent effects on ICF volume and ECF osmolality  Infusion of Isotonic Saline  Infusion of “Solute-Free” Water  Ingestion of Pure NaCl Salt  Whole-body Na+ content determines ECF volume, whereas whole-body water content determines osmolality  The epithelial cell generally has different electrochemical gradients across its apical and basolateral membranes  Epithelial cells can absorb or secrete different solutes by inserting specific channels or transporters at either the apical or basolateral membrane  Epithelia can regulate transport by controlling transport proteins, tight junctions, and the supply of the transported substances  Increased Synthesis (or Degradation) of Transport Proteins  Recruitment of Transport Proteins to the Cell Membrane  Post-translational Modifi cation of Preexisting Transport Proteins  Changes in the Paracellular Pathway  Luminal Supply of Transported Species