Potassium channels, closing

Antidiabetic Drugs other than Insulin. Figure 1 Sulphonylureas stimulate insulin release by pancreatic (3-cells. They bind to the sulphonylurea receptor (SUR-1), which closes Kir6.2 (ATP-sensitive) potassium channels. This promotes depolarisation, voltage-dependent calcium influx, and activation of calcium-sensitive proteins that control exocytotic release of insulin. 

The mu, delta and kappa opioid receptors are coupled to G° and G proteins and the inhibitory actions of the opioids occur from the closing of calcium channels (in the case of the K receptor) and the opening of potassium channels (for /i, d and ORL-1). These actions result in either reductions in transmitter release or depression of neuronal excitability depending on the pre- or postsynaptic location of the receptors. Excitatory effects can also occur via indirect mechanisms such as disinhibition, which have been reported in the substantia gelatinosa and the hippocampus. Flere, the activation of opioid receptors on GABA neurons results in removal of GABA-mediated inhibition and so leads to facilitation. 

Coupling of the receptors is very similar with all three coupling to Gq and increasing IP3/DAG and in a number of neuronal systems it has been shown that the receptors produce slow depolarising responses via the closing of potassium channels. 

This peptide itself has no selectivity for the two CCK receptors, CCK-A and B, which have so far been established to stimulate IP3/DAG while, like substance P, can close potassium channels to increase neuronal activity. The CCK-B receptor is thought to predominate in the CNS but species differences may make this interpretation difficult. It has a wide distribution in the CNS but is also found in the gut whereas the CCK-A receptor is more restricted but is found in the hypothalamus, hippocampus and in the brainstem. There are high levels of the natural peptide, CCK-8 in cortex, hippocampus, hypothalamus, ventral tegmentum, substantia nigra, brainstem and spinal cord. CCK is one of the most abundant peptides in the brain and CCK co-exists with dopamine, substance P, 5-HT and vasopressin. Interestingly, in the dopamine areas, CCK co-exists in the mesolimbic pathways but in the nigrostriatal projections, the peptide and... 

Fig. 6.21 Joint application of patch-clamp and voltage-clamp methods to the study of a single potassium channel present in the membrane of a spinal-cord neuron cultivated in the tissue culture. The values indicated before each curve are potential differences imposed on the membrane. The ion channel is either closed (C) or open (O). (A simplified drawing according to B. Hille)...

Fig. 6.24 A hypothetic scheme of the time behaviour of the spike linked to the opening and closing of sodium and potassium channels. After longer time intervals a temporary hyperpolarization of the membrane is induced by reversed transport of potassium ions inside the nerve cell. Nernst potentials for Na+ and K+ are also indicated in the figure. 

Figure 9.4 Structures of potassium channels in open and closed conformations. The selectivity filter is orange, and the conserved glycine residue is in red. (From Yu et al., 2005. Reproduced with permission of Blackwell Publishing Ltd.)...

Other potassium channels also play important roles here. For example, Kv4.3/ KChIP complex conducts the transient outward current, Ito, responsible for the descending phase 1 of the cardiac action potential, whereas Kvl.5 is underlying the ultra rapid delayed rectifying current, IKur, responsible for descending phase 2. Finally, inward rectifier potassium channel (Kir2 family) is responsible for IKl current, which maintains the action potential close to or at the resting level (phase 4). 

Repaglinide en nateglinide are not sulfonylurea agents but their mechanism of action is very alike. Repaglinide is the first carbamoylmethyl-benzoic acid derivative that has been registred for the treatment of diabetes mellitus. It closes ATP-dependent potassium channels in the beta cell membrane with consequent depolarization, opening of calcium channels and increased insulin release. It is rapidly absorbed with peak plasma levels after 1 hour. It has a protein binding of over 98%. 

The excitable membrane of nerve axons, like the membrane of cardiac muscle (see Chapter 14) and neuronal cell bodies (see Chapter 21), maintains a resting transmembrane potential of -90 to -60 mV. During excitation, the sodium channels open, and a fast inward sodium current quickly depolarizes the membrane toward the sodium equilibrium potential (+40 mV). As a result of this depolarization process, the sodium channels close (inactivate) and potassium channels open. The outward flow of potassium repolarizes the membrane toward the potassium equilibrium potential (about -95 mV) repolarization returns the sodium channels to the rested state with a characteristic recovery time that determines the refractory period. The transmembrane ionic gradients are maintained by the sodium pump. These ionic fluxes are similar to, but simpler than, those in heart muscle, and local anesthetics have similar effects in both tissues. 

Regarding the pH sensor, the carboxy tail length has been demonstrated as a determinant of pH sensitivity [Liu et al., 1993]. Further investigations [Morley et al., 1996] revealed a new model of intramolecular interactions in which the carboxy terminal serves as an independent domain that, under certain conditions, can bind to another separate domain of the connexin protein (e.g. a region including His-95) and close the channel, comparable to the ball-and-chain model for potassium channels. In this receptor (His-95),... 

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