1There are 2 major classes of ion channels in cell membranesA) Voltage-gated ion channels (VGC) require a change in membrane potential for the ion channel to open or close (RMP & AP)B) Ligand-gated ion channels (LGC) require a neurotransmitter (NT = ligand) to bind to a receptor (R) on the ion channel before the channel opens (EPP, EPSP’s & IPSP’s)+outsideinsideRNT (ligand)2A family tree of voltage-gated channelsFig. 7-9 B&B3Fig. 7-12a B&BThe amino acids indicated by the solid circles are key determinants of the ion selectivity of the channel. Model of the voltage-dependent Na+channel protein. Intra-membrane cylinders 1-6 representhelices and there are 4 repeats (domains). pseudotetramer4Fig. 7-12c BBK+channeltetramer5Fig. 7-11c BB6Fig. 7-11a BB7Voltage Sensor and Pore Domain of K+ ChannelFig. 7-10 BB8SUMMARY OF ION CHANNELS1. Voltage-gated ion channels for Na+, K+, and Ca++are all part of one super-family.2. Each ion channel consists of 4  subunits (or one pseudotetrameric  subunit in the case of Na+ channel). Additional subunits (e.g. ) help provide selectivity, regulation, etc. 3. For a given ion, there are several types (isoforms) of each channel that are distributed differently among the cells of the body.4. Each ion channel has a pore that is either open or closed depending on the position of subunits (gates).5. Later on, we will discuss a number of drugs and poisons that block channels for specific ions and disrupt normal cellular function.6. Whether a drug or poison blocks a channel depends on the isoform (subtype) of that channel. For example, tetrodotoxin blocks Na+channels in neurons and skeletal muscle cells but not in the heart.9GENERATION OF ACTION POTENTIAL (AP)10+0-voltmetermv[K+][K+]+++++70+++++CE3 Na+2 K+ATP[Na+][Na+]CERMP = axonElectrical and concentration gradients for Na+ and K+ at rest (RMP)11+0-voltmetermv[K+][K+]+++++70+++++CE3 Na+2 K+ATP[Na+][Na+]CERMP = Steps required to initiate an AP1. AP’s occur only in excitable cells such as neurons and muscle cells and require the membrane potential to reach or exceed the threshold of that cellmembrane.2. In response to stimulus, changes in membrane permeability (conductance) to Na+& K+ via the opening and closing of specific voltage-gated channels generate AP.3. At rest, the axon membrane is almost impermeable to Na+(closed Na+channels) and slightly permeable to K+ (partially open K+channels).4. Thus, the RMP of -70 mV is closer to the EKthan ENa.axon12+0-voltmetermv[K+][K+]+++++70+++++CE3 Na+2 K+ATP[Na+][Na+]CERMP = A stimulus must be applied to an axon to generate an APDepolarizing electrical stimulus1. A depolarizing stimulus is applied to the membrane to produce a sub-threshold depolarization.axonSub-threshold depolarization13Time (msec)Memb. pot. (mv)0-90+100+65ENaEKRMP -70StimulusthresholdSub-threshold depolarizationThis stimulus produces a sub-threshold depolarization that is “CONDUCTED WITH DECREMENT”.Threshold = membrane potential that must be reached before an AP can be generated. It is usually 15-20 mV more positive than the RMP.14Time (msec)Memb. pot. (mv)0-90+100+65ENaEKRMP -70StimulusthresholdSub-threshold depolarizations are GRADED, NON-REGENERATIVE potentials that decay in amplitude over time and distance. Thatis, they are ‘CONDUCTED WITH DECREMENT”Graded potential = an increase in stimulus strength produces an increase in the amplitude of the depolarization.15Time (msec)Memb. pot. (mv)0-90+100+65ENaEKRMP -70StimulusthresholdAn AP is generated once the stimulus is strong enough to produce a supra-threshold depolarization. The AP is an “ALL - OR - NONE” response. Its amplitude provides NO information on the stimulus strength. APSupra-threshold stimulus16B&L Fig 5-117gNa+gNa+DepolarizationDepolarizationOnce threshold is reached a positive feedback loop develops starting with a massive increase in gNa+that leads to rapid Na+entry that is followed by more depolarization and so on. This is called “Na+activation” and it results in the rapid upstroke of the AP. Once the membrane potential reverses (+ inside) and reaches +50 mV, “Na+inactivation” occurs and gNa+rapidly decreases to almost 0.Na+entryNa+entryStart here at threshold++Na+activation and inactivation each last about 0.5 msec for a total time course of 1 msec. Na+inactivation is not shown on this diagram.18Na+Na+channelCell membrane of a neuronNa+ VGC Na+ VGC++Once threshold is reached, Na+ activation occurs and Na+ rushes into the cell19Fig. 7-12a BBModel of the voltage-dependent Na+channel protein. Intra-membrane cylinders 1-6 representhelices and there are 4 repeats (domains). The intracellular loop between III & IV acts as the inactivation gate that swings up into the channel to block Na+entry shortly after depolarization (Na+inactivation).20Time (msec)Memb. pot. (mv)0-90+100+65ENaEKRMP -70StimulusthresholdNa+ activation produces the rapid upstroke (depolarization) of the AP and Na+ inactivation starts the rapid downstroke (repolarization) of the AP. APSupra-threshold stimulusNa+activation = gNa+Na+inactivation = gNa+21+500-voltmetermv[K+][K+]+++ + +++++CE3 Na+2 K+ATP[Na+][Na+]CEDriving forces for Na+and K+ at the PEAK of the APaxonAt the peak of the AP: 1. the E and C for Na+ become opposite to each other2. the E and C for K+both drive K+out of the cellMembrane polarity is reversed at the peak of the AP22Time (msec)Memb. pot. (mv)0-90+100+65ENaEKRMP -70StimulusthresholdNa+ activation produces the rapid upstroke (depolarization) of the AP and Na+ inactivation starts the rapid downstroke (repolarization) of the AP. gK+ helps to complete the rapid repolarization.APSupra-threshold stimulusNa+activation = gNa+gNa+ &gK+gK+gK+23B&L Fig 2-524B&L Fig 5-525SEQUENCE OF STEPS REQUIRED TO PRODUCE AN ACTION POTENTIAL1. Depolarization of the axon membrane to or above the threshold potential. This is usually 15-20 mV above the RMP.2. There is a specific time sequence in the opening of ion channels.3. First: Na+ channels open for < 1 msec allowing Na+to rapidly enter the axon down both its chemical and electrical gradients producing a reversal of the membrane polarity to + inside (Na+activation and it results in a positive feedback loop).4. Second: Na+inactivation occurs before the ENais reached preventing the further influx of Na+.5. Third: K+channels open allowing K+ to rapidly leave the axon down both its chemical and electrical gradients resulting in a