Ebook General and molecular pharmacology: Part 2
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Ebook General and molecular pharmacology: Part 2
SECTION 7PHARMAC OLOGICAL CONTROL OF MEMBRANE TRANSPORTION CHANNELSMau rizio lagliti 1 a I c 1 a and Enzo WankcBy reading this chapter, you will:•Beco Ebook General and molecular pharmacology: Part 2ome familiar with rhe main principles governing function, structural organization, and Classi fcation of ion channels•Know the role(s) played by the main classes of ion channels in different organs, tissues, and cells•Know the clinical applications of drugs interfering with the function of each ion Ebook General and molecular pharmacology: Part 2channel class•Leant how functional changes resulting from drug-induced modulation of ion channels can be exploited for therapeutic purposesION CHANNELEbook General and molecular pharmacology: Part 2
S AND TRANSPORTERSEukaryotic cells use about 30% of their energy to maintain the transmembrane gradients of protons (H*), sodium (Na*), potassiumEbook General and molecular pharmacology: Part 2
induces a conformational change, resulting in exposure of the substrate on the opposite side of themembrane. The substrate concentration gradient provSECTION 7PHARMAC OLOGICAL CONTROL OF MEMBRANE TRANSPORTION CHANNELSMau rizio lagliti 1 a I c 1 a and Enzo WankcBy reading this chapter, you will:•Beco Ebook General and molecular pharmacology: Part 2her low. By contrast, ion channels contain aqueous pores through which permeating ions can flow at very high rates (>10*/s, close to the diffusion rate in water), thus generating significant currents that may rapidly change the resting membrane potential (VMST) of a cell.Both these passive processes Ebook General and molecular pharmacology: Part 2 dissipate the energy gradient established by active transporters, which pump ions across the membrane against their concentration gradients. This proEbook General and molecular pharmacology: Part 2
cess requires an energy input generally provided by ATP hydrolysis (primary active transporters). Otherwise, movement of a solute against the electrocSECTION 7PHARMAC OLOGICAL CONTROL OF MEMBRANE TRANSPORTION CHANNELSMau rizio lagliti 1 a I c 1 a and Enzo WankcBy reading this chapter, you will:•Beco Ebook General and molecular pharmacology: Part 2ort) or in the opposite t countertransport or antiporter).Enormous progresses in the structural and functional characterization of membrane transport over the last 10 15 years have made the separation line between ion channels and transporters progressively thinner. Recent studies have shown that so Ebook General and molecular pharmacology: Part 2me toxins can convert a transporter into an ion channel and that transporters and channels can coexist within the same structural family. For instanceEbook General and molecular pharmacology: Part 2
, in the “ATP-binding cassette" (ABC) family of transporters, the cystic fibrosis transmembrane regulator (CFì R. so called as it is mutated in cysticSECTION 7PHARMAC OLOGICAL CONTROL OF MEMBRANE TRANSPORTION CHANNELSMau rizio lagliti 1 a I c 1 a and Enzo WankcBy reading this chapter, you will:•Beco Ebook General and molecular pharmacology: Part 2-4 and CLC-5). Finally, within the same family. CLC-0. CLC-1. and CLC-2 are ion channels in vertebrates, whereas their bacterial counterparts behave like transporters.mổ iWicu.'ar PhwiWrtjiogi. Prwtpitt nfDvug Acrwi First Fditwm Fdired by Fihikcsca Clenwnh Slid Guido Fitnw»Al1i c 2015 Jota Wiley A S Ebook General and molecular pharmacology: Part 2ons. Inc. Published 2015 by John Wiley A Som, Inc.312 ION CHANNELSChannelCarrierExtraceluLarMH I MiintraoeibiarFIGURE 27.1 Ion channels and transporteEbook General and molecular pharmacology: Part 2
rs. The cartoon depicts the conceptual difference between ion channels and transporters For ion channels (left), ions diffuse through the open pore, wSECTION 7PHARMAC OLOGICAL CONTROL OF MEMBRANE TRANSPORTION CHANNELSMau rizio lagliti 1 a I c 1 a and Enzo WankcBy reading this chapter, you will:•Beco Ebook General and molecular pharmacology: Part 2nated so that no high conductance open pore is allowed. “SL” represents die transported substrate that binds to the binding site in the conduction pathway (Modi fed from Ref. [1]).CHARACTERIZATION AND FUNCTIONOF ION CHANNELSIn excitable cells like muscle cells, endocrine cells, and neurons. ion chan Ebook General and molecular pharmacology: Part 2nels are responsible tor generation and regulation of electrical signals required for coordinated contraction of skeletal muscle, hormonal secretion,Ebook General and molecular pharmacology: Part 2
and neurotransmitter release; furthermore, in all cells, they control cell volume and motility.With modern electrophysiological and molecular biology SECTION 7PHARMAC OLOGICAL CONTROL OF MEMBRANE TRANSPORTION CHANNELSMau rizio lagliti 1 a I c 1 a and Enzo WankcBy reading this chapter, you will:•Beco Ebook General and molecular pharmacology: Part 2cterized. Besides suggesting the molecular basis for the action of specific drug classes, these studies have also allowed to discover that genetically determined ion channel defects can be responsible for several human diseases (the so-called human channelopathies; see Table 27.1).To understand the Ebook General and molecular pharmacology: Part 2mechanism of action of drugs acting on ion channels, it is essential to recapimlate some fundamental concepts on the functional and structural propertEbook General and molecular pharmacology: Part 2
ies of ion channel proteins.Channel Classification According to PermeatingIons and Gating MechanismsIon channels can be classified according to purelySECTION 7PHARMAC OLOGICAL CONTROL OF MEMBRANE TRANSPORTION CHANNELSMau rizio lagliti 1 a I c 1 a and Enzo WankcBy reading this chapter, you will:•Beco Ebook General and molecular pharmacology: Part 2 flowing through it.In voltage-gated ion channels (VGICs). representing the third largest class of proteins involved in signal transduction, the gating trigger is represented by changes in transmembrane voltage; even few millivolts can drastically alter the opening probability’ of VGICs. Other gatin Ebook General and molecular pharmacology: Part 2g mechanisms are represented by changes in the chemical composition of the intra- or extracellular environment (ligand-gated ion channels (LGICs): seeEbook General and molecular pharmacology: Part 2
Chapter 16). in the applied mechanical force (mechanosensitive channels), or in the envữomnental temperature (thermosensitwe channels). Obviously, thSECTION 7PHARMAC OLOGICAL CONTROL OF MEMBRANE TRANSPORTION CHANNELSMau rizio lagliti 1 a I c 1 a and Enzo WankcBy reading this chapter, you will:•Beco Ebook General and molecular pharmacology: Part 2ogical states; for example. Camdependent K* channels are also sensitive to changes in transmembrane voltage, some VGICs are also sensitive to changes in osmotic pressure, and some LGICs are also influenced by changes in transmembrane voltage and environmental temperature.Permeation characteristics a Ebook General and molecular pharmacology: Part 2llow classifying ion channels based on their ion selectivity- (with Na-. K*. Ca:*. and Cichannels showing the greatest selectivity). Further classificEbook General and molecular pharmacology: Part 2
ation criteria, such as cell- or tissue-specific expression or peculiar sensitivity to drugs and toxins, can further contribute to characterize ion chSECTION 7PHARMAC OLOGICAL CONTROL OF MEMBRANE TRANSPORTION CHANNELSMau rizio lagliti 1 a I c 1 a and Enzo WankcBy reading this chapter, you will:•Beco Ebook General and molecular pharmacology: Part 2functional properties.Permeation and Concentration GradientsIon channels having the same selectivity are often discriminated based on their conductance (Ỵ). which is the ratio between current carried (i) and electromotive force (V). the latter defined as the sum of the electrical and chemical gradie Ebook General and molecular pharmacology: Part 2nt acting on the ion. In fact, each ion is subjected to both electrical forces (the membrane potential VM is the difference between the cytoplasmic anEbook General and molecular pharmacology: Part 2
d the extracellular charges) and diffusional forces (produced by the ion concentration gradient between the intracellular and extracellular space). ThSECTION 7PHARMAC OLOGICAL CONTROL OF MEMBRANE TRANSPORTION CHANNELSMau rizio lagliti 1 a I c 1 a and Enzo WankcBy reading this chapter, you will:•Beco Ebook General and molecular pharmacology: Part 2ntration ratio between the extracellular and intracellular environment. according to the equationSECTION 7PHARMAC OLOGICAL CONTROL OF MEMBRANE TRANSPORTION CHANNELSMau rizio lagliti 1 a I c 1 a and Enzo WankcBy reading this chapter, you will:•BecoGọi ngay
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