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Membrane Transport Proteins And Ion Channels

Membrane Transport Proteins And Ion Channels
Proteins provide several routes for the movement of materials across membranes: (i) large pores, constructed of several protein subunits, that allow the bulk flow of water, ions and sometimes larger molecules (e.g. aquaporin, Chapter 34; and the connexins, that combine on the connexons to form gap junctions between cells); (ii) transporter molecules, some of which use metabolic energy (either direct or indirect) to move molecules against chemical and/or electrical gradients; and (iii) ion channels, specialized to allow the passage of particular ion species across the membrane under defined conditions.

Membrane Transport Proteins And Ion Channels

Carrier-mediated transport
Transporter (or carrier) proteins can move a single type of molecule in one direction across a membrane (a uniporter), several different molecules in one direction (a symporter) or different molecules in opposite directions (an antiporter) (Fig. 4a). Transporters can allow the movement of molecules down chemical concentration gradients (facilitated diffusion), when the energy required for conformational changes in the transporter protein is provided by the concentration gradient rather than by metabolic activity. Important transporters for glucose and amino acids, found in the kidney and the gut, are in fact driven by the Na+ electrochemical gradient that exists across the cell membrane (Chapter 2). These symporters must bind Na+ and the primary transported molecule at the external surface of the membrane before the conformational change will take place. Antiporters such as the Na+–Ca2+ exchanger similarly use the Na+ gradient, in this case to extrude one Ca2+ out of the cell in exchange for three Na+ into the cell. These processes are known as secondary active transport, as the Na+ gradient is set up by a process requiring metabolic energy. The uneven distribution of Na+ ions across the cell membrane is produced by the best known of all transporters, the Na+–K+ ATPase, also known as the Na+ pump (Fig. 4a). This protein is an antiporter that uses metabolic energy to move Na+ ions out of the cell and K+ ions in, against their respective concentration gradients. The ATPase binds extracellular K+ and intracellular Na+ ions, usually in the ratio of 2:3, and hydrolyses adenosine triphosphate (ATP) to provide the energy needed to change its conformation, leading to the ejection of Na+ into the extracellular medium and K+ into the cytosol; this allows the cell to maintain a high concentration of K+ ions and a low concentration of Na+ ions inside the cell (Chapter 2). The Na+ pump works continuously, although its activity is stimulated by high intracellular levels of Na+ ions and can be modulated by second messenger-mediated phosphorylation. The action of the Na+-K+ ATPase is the most important example of primary active transport.

Ion channels
Ions can diffuse across cell membranes down their electrochemical gradient through ion channels. These transmembrane proteins, which are invariably constructed of several subunits containing several mem- brane-spanning domains (e.g. Fig. 4b), provide a charged, hydrophilic pore through which ions can move across the lipid bilayer. They possess a number of important features that confer upon the cell the ability to control closely the movement of ions across the membrane. Ion channels are selective for particular ions, i.e. they allow the passage of only one type of ion or a few related ions. There are numerous specialized channels for Na+, K+, Cl− and Ca2+ ions, as well as non-specific channels for monovalent, divalent or even all cations (positively charged ions) or anions (negatively charged ions). The charge on the transmembrane pore determines whether the channel is for cations or anions, and selection between different ion types depends on the size of the ion and its accompanying water of hydration. Different types of channel for the same ion can however allow greatly differing amounts of that ion to move through them per second for the same electrochemical gradient; this is called channel conductance, and is best understood in the following way. Ions carry charge and so their movement causes an electrical current. Ohm’s law states that V (voltage) = I (current) × R (resistance). In terms of ion channels, V = membrane potential and I = ionic current, so one can calculate the resistance of the channel. The reciprocal of resistance is conductance, which has units called Siemens; 1 Siemens (S) = 1/Ohm. Single ion channels generally have conductances in the 2–300 pS (10–12 S) range.

The second key feature of ion channels is that their pores are either open or closed; the transition between these states is called gating. Gating is brought about by a change in the conformation of the protein subunits that opens or closes the ion-permeable pore (e.g. Fig. 4b). Many channels are opened or closed according to the potential difference (voltage) across the cell membrane (voltage gating; Chapter 5), whereas others are gated by the presence of a specific signal molecule (ligand or receptor gating). The function of some channels may additionally be modified by phosphorylation of channel proteins by enzymes such as protein kinase C or A. The voltage-gated fast inward Na+ channel that is responsible for the upstroke of the action potential (Chapter 5) has two gates, one that opens as the cell depolarizes beyond –55 mV (its threshold) and another that shuts (inactivates) the channel as the potential becomes positive (Fig. 4c). This latter gate can only be reset by repolarizing towards the resting potential (Chapter 5). Some ligand-gated channels are directly gated by extracellular molecules, such as neurotransmitters or hormones, whereas others respond indirectly via intracellular signals, such as diacylglycerol (DAG; Fig. 4d) or cyclic adenosine monophosphate (cAMP) (Chapter 3). Specialized cells that detect changes in the internal and external environments (receptor cells) possess ion channels that are gated by the particular signal that is detected by the receptor, e.g. pH or light. The characteristics of ion channels, in concert with the activities of ion pumps, give cells the ability to control precisely the movement of ions across the cell membrane. This is crucial for many important physiological processes, including electrical signalling (Chapters 5 and 6), initiation of muscle contraction (Chapters 12 and 13) and the release of materials such as neurotransmitters, hormones and digestive enzymes.