Ligands for Channels, Pores, and Transporters

For the transfer of polar compounds, cells are equipped with ion channels, pumps and special transporters, sometimes with remarkable selectivity, but sometimes with broad promiscuity. For the biologically relevant ions (Na+, K+, Ca2+, Cl−) special ion channels allow ions to flow along a concentration gradient building up an electrochemical potential across the membrane. In resting state, a potential of −70 mV is maintained across the cellular membrane. At a potential of about −60 mV fast sodium ion channels open allowing Na+ influx and gradually shift the potential to +40 mV. The sodium channels close at this value. Repolarization results from an efflux of potassium ions through slow but highly selective potassium channels. If the membrane potential falls to more negative values than the resting state, hyperpolarization is achieved e.g. by a Cl− influx through chloride channels. In some cells, influx of Ca2+ ions through specific channels can intensify the depolarization across the membrane. KcsA potassium channels cross the membrane as tetramers with long helices. Four helices that are oriented with their N-termini into a central cavern and drag positively charged ions across the membrane. The potassium ions, coordinated with eight water molecules in a quadratic-antiprismatic geometry, pass through a selectivity filter by shedding their solvation shell. The protein perfectly replaces the water coordination sphere by backbone carbonyl oxygen atoms achieving impressive selectivity over other cations. Sulfonylureas can block the regulatory unit on a K+ channel of the pancreatic β-cells that is responsible for insulin secretion. Depolarization and repolarization of the heart muscle cells are important for correct control of the heart beat frequency. Drug molecules with a particular pattern of aromatic moieties and a central basic nitrogen can block the hERG channel, a potassium channel involved in the regulation of heart beat. A fatal arrhythmia can occur. Therefore, potential binding to the hERG channel should be avoided. Voltage-gated sodium and calcium channels contribute to the depolarization of cells. They pass through different states by changing their conformation and open or close like an iris aperture by the movement of helices with hydrophobic residues. At the center, they possess a selectivity filter and a central pore. Inhibitors can block this pore below the selectivity filter. Local anesthetics such as lidocaine bind to NaV channels, while calcium blockers such as verapamil or dithiazem or nifedipine bind to CaV channels. Ligand-gated ion channels of the Cys-loop superfamily are consisting of 20 transmembrane helices. The extracellular ligand-binding domains of pentameric geometry contains the binding sites for agonists and antagonists. Agonist binding in the contact surface between two domains, attracts the C-loop and strengthens the contact between the domains. This imparts slight rotational motion to the transmembrane helices, and the channel pore expands by several angstroms due to concerted rotation of the five innermost helices. This allows sodium, potassium, or chloride ions to pass. Allosteric regulators such as benzodiazepines form an additional contact within the pentameric domains and thus enhance the effect of the endogenous ligand GABA. The voltage-gated CIC chloride channels orient two extended helices with their N-terminal ends towards the center of the channel where a conserved glutamate takes the role of a gatekeeper. Ion pumps adjust ion equilibria against a concentration gradient. The K+/H+ ion pumps is inhibited by drugs such as omeprazole. The latter binds irreversibly covalent to Cys 813. Transporters shuffle endo- and exogenous compounds across the cell membrane. Bacteria have developed special transporter systems to either allow access to cells, or to penetrate the membrane of other organisms. The regulation of water homeostasis is performed by aquaporins. They exhibit a 15Å wide funnel-shaped vestibule and narrow to a diameter of 2.8 Å in the center. There, a His and Arg residue prevents the passage of H3O+ ions. A chain of exposed C=O and NH groups lines one side of the pore, allowing water molecules to move along H-bonds like on a rope ladder. https://sn.pub/ekembs