Biological Membranes: Structure, Receptors, and Solute Transport PDF

Biological Membranes: Structure, Receptors, and Solute Transport Thomas M. Devlin Professor Emeritus, Drexel University College ofMedicine 12.7 CLINICAL CORRELATIONS 12.1 INTRODUCJ'ION 453...

Biological Membranes: Structure, Receptors, and Solute Transport Thomas M. Devlin Professor Emeritus, Drexel University College ofMedicine 12.7 CLINICAL CORRELATIONS 12.1 INTRODUCJ'ION 453 MEMBRANE CH.'\NNELS AND PORES 477 12.1 Liposomes as Carriers of Drugs, 12.2 CHEM ICAL COM POSITION Protein3, and Nucleic f'.cios 466 OF MEM BRANES 458 12.8 MEM BRANE TRANS PORT 12.2 f'.bnormallties of Ce I Membrane PROTEINS 485 12.3 MICELLES, LIPID BILAYERS, Fluidity in Disease 472 AND LIPOSOMES 463 12.9 ELECTROCHEMJCAL- 12.3 The Mommalian Kidney and POTENTIAL-DRlVEN /\qu:~pori ns 480 12.4 STRUCT URE OF BI OLOG ICAL TRANSPORTERS 487 12.4 Diseases due to Loss cf Membrane MEMBRse: Lenon< from n1ice to hu- form normal rerramer srrucrures. Levels oi AQP I, AQP2, and AQP3 mans. Trends ill Endocrinolo!J! & Merobclimtl'>: 'ISS, 2002: Nielsen, S., Frokiaer, in animal models are reduced in tissue ischemia. In some condirions, I., Marples, D., Kwon, T·H., er al. Aq uaporins in me kidney: From molecules ro such as congestive heart failure, liver cirrhosis. and pregnancy, there medicine. Pbysiol. Rev. 82: 2C5, 2002; :nd King, L S., Kowno, K., and Agre, P. is an increase in me amounr of AQP2 in rhe kidney. leading ro an From srrucmre to disease: Thr evolving ule ofAquaponn biology. Nomre &tiews: expansion of rhe extracell ular fluid volume. Humans lacking AQP 1 Jvfolecttlar Cell Bio!ogy 5: 687, 2004. (a.) Figure 12.35 Simulation of water permeation through AQP1. (a) The permeorion observed rhmugh rhe pore. simularion of the AQPI rerramer (orangelmagenralblur/cyan) embecded Figure reproduced wirh ?ermission from Fujiyoshi. Y., Mitsuoka, K.. de in a palmimyl oleoyl phospharidylethanolamine bilayer (yellow/green) Groot, B. L., Philippsen, A. er al. Srrucrure and function of ware rchannels. surrounded by warer (red/whire) consisred of approximarely I00,000 atoms. Curr. Opin. Srruct. Bioi. 12: 509, 2002. ©Elsevier. (b) Simularion ofrhe pathway of one of the monomers of APQI for waru  CHAPT ER 12 H J(.)LOon lead to a decrease in affinity. Finally in recovery, step 4, the transporter returns to its original co nformation on release of substrate. s, This discussion centered on movement of a single substrate by a transporter (uoi- Sz pon mechanism). There a re systems that move two substrates simultaneously in one Symport direction (sympon) and two substrates simultaneously in opposite directions (antip ort) s·1 S' 2 (Figure 12.46). When a charged substance is translocated and no ion of the opposite s, Sz charge is moved or two molecules with different charges are translocated by an antiport AntipM mechanism, a charge sepa ration occurs across the membrane. This mechanism is termed s·, S'z electrogenic tr ansp ort and leads to development of a membrane potential. If an oppo- sitely charged ion is moved to balance the charge or two molecules of the same charge are moved in opposite directions across the membrane, the mechanism is termed n eutral or Figure 12.46 Uniport, symport, and antiport electrically silent transport. mechanis ms for t ranslocation of substa nces. S and S' represent d ifterenr molecules. Energetics of Membrane Transport Systems Eq. 12.2 gives the change in free energy when an uncharged molecule moves from concen- tration Cl to concentration C2 on the other side of a membrane. L1 G'= 2.3RT1og ( g~ ) (12.2) When L1 G' is negative- that is, there is release of free energy- movement of solute occurs without the need for a driving force. When L1 G' is positive, as would be the case if C 2 is larger than C 1, then rher·e needs to be input of energy to drive the transport. For a charged molecule (e.g., N a+) both the dcctrical potential and concentrations of sol ute arc involved in calculating the change in free en erg( as indicated in Eq. 12.3 L1 G'= 2.3RT1og( g) +Zf¥ !1'/f (12.3) where£1 G' L~ electrochemical pmenria!, Z is charge oi the transported species, :!F is Faraday constant (96.49 kj/V/mol, 23.06 kcal/V/mol), and L1'fr is electrical potential d ifference in volts across the membrane. The magnitude and sign of both Z and L1 tJr influence L1 G'. When L1 (," is negative movement of solute occurs spontaneously; this is often referred to as passive transport. When L1 G' is positive, input of energy from some source is required and the process is called active transport.  CHAPT ER 12 H J(.)LO gt>nt'.< for rh~ C.i.lJT TABLE 12.11 Representative Substrates for Membrane Transport Protein s in Eukaryote& Inorgan ic cations H +. K-t, Na +, NH/. Ca2+, CoH , CuH. FeH. Mg2 +, Zn2+ Inorganic anions Cl - , HCO; - , SOi - , iodide, phosphate, arsenice Sugars Fructose, glucose, hexoses, lactose, maltose, myo-inositol Organ ic acids Aca:ate, bile acids, bilirubin, citrate, glucose G-phosphate, a-ketoglutarate, !aerate, malare, oxala:etate, prostaglandins Amino x ids Acid ic, b:>Sic, neutral, branched chain Peprideslproteins Some Nudeosides/ nudeotides ATP, ADP, all others V!tamins/cofacrors Ascorbate, biotin, folace, lipoate , thiamin Drugs Multiple drugs So11rce:.\1o5s, G. P. Membrar.e Transporr Proreins. hrt?://www.chem.qmul.~c.uk/iubmb/mrp/  CHAPT ER 12 H J(.)LO-+-transporti ng ATPase. Conformational changes of the Ca2+· transporting A TPase of the sarcoplasmic reticulum. Poinu of entry and exir of Ca2 + are hown by the purple onnw Figur n n rhe II'~ i.< wi1h hn11nrl C:o2+ , onrl nn rhe righ t wi rhm ~r C:o2+. Rqroduced wirh permission from Toymhima. C.. and lnesi. G. Snucural basis of ion pumping by Ca2+- ATPase of rhe sarcoplasmic reticulum. Anmt. Rev. Bicchem. 73: 269, 2004. Copyrighi (2004) Annual Reviews; \liWW.annualreviews.org. 494 PAR I HI l:'UNCl'lONS Or PROTEINS transporrer, lowering the /(,11 for Cal 1 from abom 20 ro 0.5 ,uM and increasing Ca2 1 trans- pon. Increased acrivity reduces cytosolic ci+ to irs normal resting level (- 0.10 pM) at which concentration the Ca2 +- calmodulin complex dissociates and the rate of Ca2+ trans- port returns to its basal value. ATP~ Other cellular processes are also regulated by rhe Ca2+- calmodulin complex. Cal- modulin is one of several Ca2+ -binding proteins, including parvalbumin and tro- ponin C. which have very similar structures. Calmodul in (17 kDa) has the shape of a cl11rnhhell wirh rwo g lnh11br enrl.< cnnnec.rerl hy ~ seven-rmn tY-helix; ir Sa polypeptide of 1480 amino steatorrhea (faery stool); see page I 032 for a discus~ ion of the role of ~cids with structural homology to the superfamily of ATP- binding the pancreas in fat digestion and absorprio11. CF patients have re- cassette (ABC) transporters. T he gene has been cloned, and a major d uced Cl- permeabili ty that impai:s fluid and clccrrolyrc secretion, effort is under way to treat the disease by gene therapy, ttsing both vi- leading w luminal J thyillariun. Diagnosis of CF is tonll rmtJ by a ral ami nun viral voctors indmli ng liposo mts (stt Clin. Corr. 12.1). significanr increase of Cl - conrenr of swear of affected in com pari- son ro normal individuals. Kttnzelmann, K., and Mall, M. l' harmacotherapy of the ion uansporr defect h The gene responsib le for CF was idenrifted in 1Yll9 and over llUU rysr.c fibrosis. Clin. Exp. Pharm. & f'hysiol. 28: 857, 200: ; Zeidin, P. l. T hera- pies directed '" chc basic defect in cystic Fibrosis. Clilti,·s in Che;e M