Sodium Na+ Channel - Lab Report Example

Sodium Na+ channel Introduction Using computer simulation software obtained from Labheart.org we performed simulation studies by varying Na conductance and obtaining action potential AP curves in rabbit myocytes(muscle cells). .Figure 1. Lab Heart Version 4.9.2 Methods The upstroke of ventricular AP results from activation of a large concentration of sodium current (Ina). However the AP will only occur until the appropriate threshold current in applied. Following instructions in the Labheart program we simulated cell conductance and obtained the following results. Results 1- line graphs (1,2,3) illustrate the changes in conduction (G) of Na affect the overall action potential and the component currents. Graph 1: AP when GNa4 Graph 2: AP When GNa8 Graph 3: AP when GNa 14 2- Line graph (4) By Use several different conductance values. Current voltage relationship (I-V plot) to illustrate the conduction change effects. Graph 4: I-V plot Red when GNa 14, Green when GNa 8, Purple when GNa 4 The drug TTX was tested for its ability to block conductanceand the were as follows: When the GNa 15 we need 70% TTX When the GNa 14 we need 68% TTX When the GNa 8 we need 40% TTX When the GNa 4 we need 1% TTX When The GNa 2 we need 1% TTX Discussion The heart can only beat if electrically charged particles(ions) are transported back and forth across the plasma membrane of the heart cells. The Sodium-potassium pump conducts this activity by pumping potassium into the cell and sodium out. Indirectly it also controls the concentration of calcium which in tur controls the heartbeat. Patients with cardiac insufficiency receive drugs that affect the sodium pump in order to stabilize the heartbeat The Sodium Channel Voltage-gated channels open and close in response to membrane potential. Voltage-gated sodium channels. The family consists of at least 9 members and is largely responsible for action potential creation and propogation. The pore-forming alpha subunits are very large(up to 4,000 amino acids) and consist of four homologous repeat domains, comprising six transmembrane segments and transverse the cell membrane 24 times. They coassemble with a beta subunit that spans the membrane. Scorpion toxin has been used for classification of these channels. Diagram of a voltage-sensitive sodium channel α-subunit. G - glycosylation, P - phosphorylation, S - ion selectivity, I - inactivation, positive (+) charges in S4 are important for transmembrane voltage sensingFrank H. Yu and William A. Catterall (2003) "Overview of the voltage-gated sodium channel family" in Genome Biol. 4(3): 207. ([http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153452 Full text online]). Sodium Channel Blockers Extracellular The following naturally produced substances block sodium channels by binding to and occluding the extracellular pore opening of the channel: Alkaloids- Tetrodotoxin(TTX) Saxitoxin Class Ia agents depress phase 0 depolariztion and reduces Vmax which prolongs the action potential duration by slowing conductance, these agents include quinidine, procainamide, and disopyramide and should be used in conjunction with a AV node blockig agent such as digoxin or a beta-blocker. Class Ib agents have fast oset and offset kinetics and little or no effect at slower heartbeats. These include lidocaine, mexiletine, toccainide, and phenytoin. Class Ic agents markedly depress the phas 0 depolarization. They are indicated for lif-threatening ventricular tachycardia or ventricular fibrillation and for the treatment of atrial fibrillation. They are potentially pro-arrhythmic, especially in settings of structural heart disease, as in post myocardial infarction and contraindicated in such instances. These agents includeencainide, flecaimide, morizine, and propafenone. A few classII agents have a stabibilizing effect on the cell membrame. Such as propranadol.1 1)Web Site Wikipedia The Sodium Channel http://en.wikipedia.org/wiki/Sodium_channel_blockers The Sodium Pump The Na+-K+-ATPase is a highly-conserved integral membrane protein that is expressed in virtually all cells of higher organisms. As one measure of their importance, it has been estimated that roughly 25% of all cytoplasmic ATP is hydrolyzed by sodium pumps in resting humans. In nerve cells, approximately 70% of the ATP is consumed to fuel sodium pumps. Physiologic and Pathologic Significance The ionic transport conducted by sodium pumps creates both an electrical and chemical gradient across the plasma membrane. This is critical not only for that cell but, in many cases, for directional fluid and electrolyte movement across epithelial sheets. Some key examples include: The cell's resting membrane potential is a manifestation of the electrical gradient, and the gradient is the basis for excitability in nerve and muscle cells. Export of sodium from the cell provides the driving force for several facilitated transporters, which import glucose, amino acids and other nutrients into the cell. Depending on cell type, there are between 800,000 and 30 million pumps on the surface of cells. They may be distributed fairly evenly, or clustered in certain membrane domains, as in the basolateral membranes of polarized epithelial cells in the kidney and intestine. Abnormalities in the number or function of Na+-K+-ATPases are thought to be involved in several pathologic states, particular heart disease and hypertension. Well-studied examples of this linkage include: Several types of heart failure are associated with significant reductions in myocardial concentration of Na+-K+-ATPase. Excessive renal reabsorption of sodium due to oversecretion of aldosterone has been associated with hypertension in humans. Structure and Function The Na+-K+-ATPase is composed of two subunits. The alpha subunit (~113 kD) is the action hero of the pair - it binds ATP and both sodium and potassium ions, and contains the phosphorylation site. The smaller beta subunit (~35 kDa glycoprotein) is absolutely necessary for activity of the complex. It appears to be critical in facilitating the plasma membrane localization and activation of the alpha subunit. Several isoforms of both alpha and beta subunits have been identified, but aside from kinetic characterizations and tissue distribution, little is known regarding their differential physiologic importance. Uncertainties remain in describing the structure of this molecule, but based on primary amino acid sequence, it is thought to possess 8 or 10 transmembrane domains. Considerable information is available to define the amino acids involved in ATP and cation binding. Cation transport occurs in a cycle of conformational changes apparently triggered by phosphorylation of the pump. As currently understood, the sequence of events can be summarized as follows: The pump, with bound ATP, binds 3 intracellular Na+ ions. ATP is hydrolyzed, leading to phosphorylation of a cytoplasmic loop of the pump and release of ADP. A conformational change in the pump exposes the Na+ ions to the outside, where they are released. The pump binds 2 extracellular K+ ions, leading somehow to dephosphorylation of the alpha subunit. ATP binds and the pump reorients to release K+ ions inside the cell. The pump is ready to go again2 2)(Web Site) The Na+-K+-ATPase Channel(Sodium Pump) http://www.vivo.colostate.edu/hbooks/molecules/sodium_pump.html Conclusions Our computer simulation experimental studies showed an increase in Na conductance increase the Action Potential of cellular polarization. Literature research then characterized the sodium channels molecular structure, as well as explaining there contribution in maintaining cellular ionic balance, as well as fluid balance. Drugs were characterized and listed that act as sodium channel blockers and are used daily around the world in the treatment of heart disease. Read More