THE ACTION POTENTIAL THE RESTING POTENTIAL A molecular complex, sodium-potassium ATP-ase, burns ATP to pump 3 sodium ions OUT of the nerve cell for every 2 potassium ions pumped IN Hence more sodium outside, potassium inside There is consequently a voltage across the neuronal cell membrane, with a resting potential of roughly 72 millivolts, positive outside THE ACTION POTENTIAL (also called the NERVE IMPULSE) Sometimes passive current spread reduces the voltage at the axon hillock to 52 millivolts This DEPOLARIZATION is excitatory in the sense that it can cause the neuron to spike or fire When depolarization reaches some THRESHOLD, often -52 mV At this point the specialized membrane FIRES A localized region suddenly goes positive as much as 50 mV Then just as rapidly goes negative again Following which there is a brief OVERSHOOT + during which time the membrane is REFRACTORY to stimulation Then return to resting potential, ready to fire again VOLTAGE-GATED ION CHANNELS These through-membrane channels OPEN when membrane potential reaches some THRESHOLD This opening is called ACTIVATION Often, they then close again just as quickly: this process is DEACTIVATION The ACTION potential is due to: A rapid opening and closing of a sodium channel Causing sodium to rush into the cell, bringing voltage briefly to +50 mV A later, slower opening and closing of potassium channels, allowing potassium to leave the cell Helping potential to return to resting potential, and accounting for the overshoot and the refractory period VOLTAGE-GATED ION CHANNEL ACTIVATION: Allows passage of a single ionized element, usually: i. Sodium ii. Calcium iii. Chlorine iv. Potassium These ions move DOWN electrochemical gradients Hence ion movement requires almost no direct energy! There are currently over 70 known voltage gated ion channels! THE VOLTAGE-GATED SODIUM CHANNEL: Has four subunits, each a large molecule Each subunit has 6 transmembrane domains The 4 subunits surround the ion channel One of the 4 subunits is the VOLTAGE SENSOR + Changes conformation, opening the channel, when the axonal membrane is depolarized. Another 2 subunits form the DEACTIVATION GATE + Thought to be a kind of cork, dangling from a support on the inside of the cell membrane + Promptly after ACTIVATION, the membrane alters shape, inserting the "cork" into the channel, hence closing it The consequence is that the sodium channel is open only briefly! THE VOLTAGE-GATED POTASSIUM CHANNELS THESE COME IN MANY FLAVORS Over 50 are known! In consequence, there are MANY forms of the action potential, specific to regions, individual neurons, or even parts of individual neurons THE Na+/K+ PUMP PLAYS NO DIRECT ROLE IN THE ACTION POTENTIAL The ionic movements occur very close to the cell membrane And a single action potential involves movement of far less than 1 % of the ions on either side of the membrane Plus the sodium/potassium pump is quite slow compared to the action potential MYELIN SHEATH AND NERVE IMPULSE CONDUCTION There are no voltage-gated sodium pumps on the axonal membrane enveloped by the myelin sheath They are concentrated on axonal membrane at the node of Ranvier + Thus the nerve impulse is conducted passively, by ionic diffusion, between nodes + This greatly increases the speed of nervous conduction! VOLTAGE-GATED CHANNELS AND DRUGS: + Lidocaine blocks Na channels, hence the action potential + Anesthetics may jam the K+ channel open DRUG ACTION AT BINDING SITES IN THE BRAIN VIRTUALLY ALL DRUGS ACT BY BINDING TO ENDOGENOUS COMPOUNDS IN THE BRAIN THERE ARE 4 MAJOR TYPES OF BINDING SITES: I. NEUROTRANSMITTER RECEPTORS A. Ion Channels - FAST transmission B. Second Messenger Systems - SLOW transmission II. NUCLEAR DNA BINDING SITES - Relatively rare for phsycopharmaceuticals, COMMON for hormones! III. TRANSPORTERS - Especially neurotransmitter reuptake sites IV. ENZYMES NEUROTRANSMITTER RECEPTORS: RECEPTOR CONFIRMATION + Receptors are complex proteins, in long chains + These chains weave in and out of the cell/neuronal membrane + Hence have three parts: extracellular, Transmembrane, and intracellular segments The extracellular segment often contains the "recognition" or binding site for the neurotransmitter The transmembrane segment is typically a helix, and crosses the membrane numerous times; often 7 for hormone and second-messenger receptors, 5 for many ion channels The Intracellular segment typically comprises cytoplasmic loops, formed when the protein leaves and then re- enters the cell membrane, and a large terminal component inside the cell + These intracellular components often trigger second- messenger systems RECEPTOR-ACTIVATED ION CHANNELS: Typically PASSIVE - like other ion channels, allow passage of a single ionic substance Can form complexes with numerous subunits, sometimes with recognition/binding sites for a VARIETY of neuro- transmitters Close when the neurotransmitter dissociates from the binding site SECOND-MESSENGER SYSTEMS: MOST COMMON TYPE OF NT RECEPTOR EXTREMELY COMPLEX 1. The First messenger is the neurotransmitter 2. It binds to the extracellular receptor site and causes a CONFORMATION change in the intracellular segment of the receptor 3. This change allows a protein inside the cell to bind to the altered intracellular receptor site. 4. This protein, known as a G protein, is often either cyclic adenosine monophosphate (cAMP) or phosphatidyl inositol (PI) 5. The receptor-G protein complex then activates one or more enzymes 6. And the enzymes then produce the true SECOND MESSENGER THIS COMPLEX INTERACTION CAN BE SYMBOLIZED AS: NT ->RECEPTOR ->G PROTEIN/RECEPTOR COMPLEX -> ENZYME -> SECOND MESSENGER This second messenger can trigger a further cascade of events! This whole cascade can ultimately produce intracellular enzymes, or activate DNA, thus either turning off or on production of a range of cell products TRANSPORTERS ALSO SIT ON CELL MEMBRANE COMMONLY CONTAIN A BINDING SITE AND A LINK TO ATP THUS BIND EXTRACELLULAR NEUROTRANSMITTER, AND BURN ATP TO DRAG THE NEURO- TRANSMITTER INTO THE CELL