Passive+Membrane+Properties

=**Passive Membrane Properties**=


 * 1. Understand the fluid-mosaic structure of the plasma membrane and the concept that ion channels and pumps contribute to specialized membrane function.**

Plasma membranes are composed of a 3-5 nM thick lipid bilayer in which membrane-associated and transmembrane proteins are embedded. This notion of a “sea of lipids” containing mobile “islands” of membrane proteins is known as the fluid-mosaic model of plasma membranes. Two important classes of membrane proteins are ion channels and ion pumps. Ion channels fall into several categories, some of which confer neurons the excitability property and sustain the resting membrane potential.


 * 2. Understand the basic structure and classifications of ion channels.**

Resting and action potentials are generated by ions traversing the cell membrane by way of ion channels. This movement of ions proves the basis of electrical signaling.

Ion channels are transmembrane proteins embedded in the lipid bilayer that contain an aqueous pore allowing ions to permeate the plasma membrane. Thus, this channel functions as an electrical conductor with resistance. The size of the pore, and its internal properties governs the ion channel’s resistance and its selectivity for specific ions. Because of the different electrical properties of membrane lipids and ion channels, a cell membrane can be modeled as an electrical circuit with capacitors (lipids) and resistors (ion channels) wired together in parallel. The capacitive properties of the membrane allow it to store charge, while the resistive elements provide a pathway for ions to cross the membrane and change the membrane potential during electrical signaling. There are 4 major classes of ion channels.

Voltage-gated ion channels are single polypeptides with 4 subunits. Each subunit contains 6 transmembrane regions and a hairpin loop between S5/S6 which lines the central pore. The pore of voltage-gated channels is opened or closed depending on the membrane potential and are very selective for their particular ions.

Ligand-gated ion channels are composed of individual subunits, each composed of 4 membrane spanning regions with M2 lining the channel pore. For example, acetylcholine receptor channels is made up for 5 subunits.The pore of these channels is gated by the binding of a ligand (usually a neurotransmitter). Ligand-gated channels are much less selective for ions than voltage-gated channels but are generally valence selective.

Gap junction channels are paired channels of connexons that meet across membrane junctions. They provide an aqueous pathway to connect adjacent cells. They are responsible for electrical coupling between hepatocytes, smooth muscle cells, and cardiac myocytes, and less evident in mammalian nervous systems. They are generally non-selective because of their large pore size and are weakly gated by pH and/or Ca2+. The pore is so large, it can also accommodate transfer of large metabolites and nucleic acids.

Leak channels are non-gated channels, can be selective for specific ions, and are open all the time. They govern the passive properties of plasma membranes such as resting potential.


 * 3. Be able to define current, voltage, resistance, capacitance, depolarization, and hyperpolarization.**

Current (I) is the flow of electrical charge measured in amperes. Voltage (V) is the difference of electrical potential between two points of an electrical or electronic circuit, expressed in volts. Resistance (R) is a measure of the degree to which an object opposes the passage of an electric current, measured in ohms. Capacitance (C) is a measure of the amount of electric charge stored (or separated) for a given electric potential and is measured in farads. Capacitance is equal to the charge divided by the potential.

Depolarization is a decrease in the absolute value of a cell’s membrane potential such that it becomes less positive or less negative. Hyperpolarization is an increase in the absolute value of a cell’s membrane potential such that is becomes more positive or more negative.


 * 4. Be able to describe the way concentration and voltage determine the driving force on ions in solution.**

Passive membrane potentials and action potentials are established by ions crossing cell membranes through ion channels. Particles concentrated in one place tend to diffuse over time to become equally distributed in the available space. Since ions are charged particles, both the voltage and concentration gradients that they experience will influence their movements. Ions are able to permeate cell membranes via ion channels will diffuse down their concentration gradients, traveling from an area of high concentration (Compartment A) to one of lower concentration (Compartment B). If the ion is positively charged, there would be a less loss of positive charge in Compartment A, resulting in Compartment A becoming negative with respect to Compartment B, establishing a voltage gradient. This sets up an electrochemical equilibrium such that the concentration gradient pushing the ion from Compartment A to B is exactly balanced by the voltage gradient pushing the ion from Compartment B to A. The driving force that pushes an ion through its channel depends on the concentration gradient of the ion across the membrane and the potential difference (voltage) across the membrane. If the concentration gradient and potential difference are equal and opposite, there would be no net current flow and the system is in equilibrium.


 * 5. Understand the special circumstance under which electrochemical equilibrium is achieved.**

A neuron’s negative resting potential is primarily governed by leak channels having a high resting permeability to an ion species. For example, K+ leaks down its concentration gradient and the leak is opposed by the resultant membrane potential. Because of the membrane’s capacitance, it takes an infinitesimal amount of K+ to establish significant voltage gradients compared to the surrounding bulk concentration.

However, under physiological conditions of low external K+, the membrane potential is slightly permeable to other ions (most notably Na+ and Cl-) which brings the membrane potential to a value slightly depolarized to the equilibrium potential of K+ (//E//K). The consequence of permeability to multiple ions is that cells are never at ionic equilibrium. Since the resting potential is slightly depolarized to Ek, there will be a net leak of K+ out of the cells and a net leak of Na+ into the cell. To counteract this problem, cells have membrane energy-driven pumps that pump K+ in and Na+ out.


 * 6. Be able to use the Nernst Equation to predict the equilibrium potential for ions distributed inside and outside of cells.**

To predict equilibrium potential for a single ion equilibrium, use the Nernst equation:

//E//x ``=`` (RT/zF) ln ( [X”] / [X’] )

where R is the gas constant, T is absolute temperature, z is the ion valence, and F is faraday’s constant.

At room temperature conditions and converting to log base 10, the Nernst equation equals:

//E//x ``=`` (58/z) log ( [X”] / [X’] )

For example, if 10 K+ ``=`` [X’] and K+ ``=`` [X”], the //E//x ``=`` (58/1) log ( 1 / 10 ) ``=`` -58 mV.


 * 7. Be able to use the Goldman Equation to explain the resting membrane potential in terms of ionic concentration gradients and selective membrane permeabilities for K+ and Na+.**

If you know the permeabilities (//P//) of the membrane to relevant ions, it is possible to predict the membrane potential in a multi-ion environment, use the Goldman equation:

V ``=`` 58 log ( //P//K[K+”] + //P//Na[Na+”] + //P//Cl [Cl-‘] ) / ( //P//K[K+’] + //P//Na[Na+’] + //P//Cl [Cl-“] )

If the membrane is permeable to only 1 of the ions in the Goldman equation, it will collapse back into the Nernst equation. When the membrane is permeable to multiple ions, they each respond independently to their respective forces. Thus, if //P//K >> //P//Na, then V is going to be closer to //E//K. If the membrane suddenly becomes permeable to Na+, such that //P//Na >> //P//K, then V shoots up close to //E//Na. This is what happens during an action potential.


 * 8. Define the two major types of ion pumps and understand the structure and function of the Na+/K+ ATPase pump.**

There are two types of ion pumps: ATPase pumps and ion exchange pumps. Na+/K+ ATPase pumps sustain the gradients such that K+ is high inside cells and Na+ is high outside. Ca2+ ATPase pump keeps the levels of intracellular Ca2+ low and helps maintain intracellular pH balance.

Ion exchange pumps use electrochemical gradients of other ions as their energy source and ultimately are dependent on the ATPase type pumps. These pumps carry one ore more ions against their concentration gradient while taking another ion down its gradient. Na+/Ca2+ exchanger pumps Ca2+ out, Cl-/HCO3- exchanger pumps Cl- out, Na+/H+ exchanger pumps H+ out.

The molecular structure of the Na+/K+ pump is an integral transmembrane protein with 10 transmembrane regions and lots of cytoplasmic loops. One intracellular domain is required for ATP binding and hydrolysis. The oubain binding site is implicated in the extracellular loop between segments 1 and 2. Where K+ and Na+ bind and how the protein changes shape is not currently known.

3 Intracellular Na+ ions bind to an exposed sit on the pump. The pump gets phosphorylated in the presence of ATP. The phosphorylated pump undergoes a conformation change, exposing the ionic binding sites to the extracellular fluid such that the 3 Na+ ions can be released and 2 K+ ions can bind. Dephosphorylation results in a reverse conformational change leading to K+ release into the cytoplasm. Because the ratio is 3 Na+ extruded for every 2 K+ recovered, the Na+/K+ pump contributes slightly to the resting potential and is electrogenic.