January 21, 2016: Ion Channels & MembranesJanuary 21, 2016: Ion Channels & MembranesSlide 3Electrical Communication: Ion ChannelsIon PumpsThe Ionic Basis of The Resting Membrane PotentialElectrical and Chemical GradientsSlide 8Equilibrium Potential for Each IonElectrical CommunicationSlide 11Slide 12Slide 13Slide 14Slide 15Slide 16Slide 17Slide 18Slide 19Slide 20Slide 21Neuropharmacology•Review last lecture: What are the building blocks of the nervous system?•Types of Neurons and GilaJanuary 21, 2016: Ion Channels & Membranes•Today: •Physiological Properties that define neurons and enable signal conduction•Ion channels•Receptors (ion and ligand-gated)January 21, 2016: Ion Channels & MembranesThe Resting Membrane PotentialThe Resting Membrane Potential•There is a voltage across the nerve cell membrane. •The voltage is caused by current flow across the membrane, as ions move through channel proteins in response to electrochemical gradients.-mV•Changes in this “resting membrane potential” are used in signaling within the nervous system. •Ions: atoms or molecules with a net electrical charge•Cations: positive charge (name some!)•Anions: negative charge (name some!)•water acts as a solvent for ions, amino acids, sugars and other molecules essential for cell functionElectrical Communication: Ion ChannelsTo Consider: What happens when mutations occur in the genes encoding ion channels? Mutations of specific K+ channels cause inherited neurological disorders.Ion Pumps•Ion pumps are formed by membrane spanning proteins•Use energy from ATP breakdown to pump specific ions against a concentration gradient•Create and enforce ionic gradients across membranes that are used for neuronal signalling•Sodium is pumped out of the cell. Therefore, sodium ions are at a low concentration inside the cell. Na/K Ion Pump (ATPase)The Ionic Basis of The Resting Membrane Potential•Membrane potential: Voltage across the neuronal membrane•Can be measured with an electrode that is connected to an amplifier•The membrane potential is relatively stable at “rest” but changes frequently due to “inputs” from other cells or the outside world•Current flow is responsible for these voltage changesElectrical and Chemical Gradients •The negative electrical potential difference across the membrane attracts positive ions inside. •Chemical concentration differences result in K+ being more concentrated inside of the cell, Na+ and Ca2+ are more concentrated outside.•Therefore, Na+ wants to move down its concentration gradient into the cell. •At rest, membrane is much more permeable to K+ which flows through many resting ion channels out of the cell keeping the cell more negative inside. •Balance between Na+ influx and K+ efflux to keep the membrane potential constant.Why are there always concentration gradients across the membrane for Na+ and K+?• Remember the sodium-potassium pump•Enzyme - breaks down ATP when Na present•Actively transports Na+ out of cytosol in exchange for K+ to make sure there is always a gradientEquilibrium Potential for Each Ion•For each ion, the equilibrium (or reversal) potential is the membrane potential in which the net flow through any open channels is 0. In other words, at Erev, the chemical and electrical forces are in balance. Erev can be calculated using the Nernst equation.•Two ions are always “duking it out” with the membrane potential swinging towards the equilibrium potential of the ion with the biggest current.Electrical Communication-mVRESTING ‘leaky’ ION CHANNELS:PERMERABLE TO POTASSIUM K+VOLTAGE-GATED CHANNELS:SODIUM ‘NA+’, POTASSIUM ‘K+’, CHLORIDE ‘Cl-’FOUND IN CELL BODIES, DENDRITIES, AXONSNaK ATP PUMP: 3 Na+ out for 2K+ inVoltage-gated ion channel:They open with respect to how much charge there is.Ligand-gated ion channelLigandTypes of Channels•Specialized amino acid sequences within the protein create functional domains that allow the protein to display appropriate ion selectivity and gating.The molecular structure of a single sodium channel. The huge protein includes 4 repeated units, each with 6 membrane-spanning regions. One specific region forms the pore, another the gate and another the voltage-sensor.Using the “patch-clamp” technique, one can measure the current through an individual channel proteins. Sodium channels have a unique feature – once open, they become “inactivated” for a time.(K+ channels open later and do not inactivate)What technique is this?It is a patch-clamp•Inactivates - so for a time cannot be open again by depolarization. This is known as the absolute refractory period: channels are inactivated, so another spike can’t occur for a few msecVoltage-Gated Sodium ChannelToxins as experimental toolsLigands: Amino acid neurotransmittersThe biogenic amine neurotransmittersMultiple receptor types for each neurotransmitter: nicotinic acetylcholine receptors are important at NMJMolecular structure of the nicotinic acetylcholine receptor: this is an ionotropic receptor because the protein includes an ion channelMetabotropic receptors (unlike ionotropic), do not have an ion channel as part of the protein structure, but instead work by activating G-proteins that are associated with the internal face of the adjacent membrane. The G-protein, in turn, modulates ion channels or intracellular signaling pathways.Once activated, the subunits of G-proteins activate other effector proteins of the target cell, such as ion channels or “second messenger” pathways inside the cell.There are multiple receptor types for each neurotransmitter: three classes of ionotropic glutamate receptors. NMDA and AMPA receptors are important for synaptic plasticity…to be discussed later.Neuropharmacology•Effect of drugs on nervous system tissue•Receptor antagonists: Inhibitors of neurotransmitter receptors•Curare, bungarotoxin, alpha-blockers, beta-blockers, strychnine•Receptor agonists: Mimic actions of naturally occurring neurotransmitters•nicotine, muscarine, AMPA, NMDA•Defective neurotransmission: cause of many neurological and psychiatric disorders•Myasthenia gravis, depression,