4 Baraa Ayed أسامة الخض Mohammad khatatbeh 1 P a g e
Today we want to talk about these concepts: Excitation-Contraction coupling Smooth muscles (Generally speaking) Excitation-Contraction coupling Excitation-Contraction coupling means how we get the excited muscle to get the contraction of this muscle. Remember that we have motor neuron that generates the action potential and this motor neuron have many terminals and each of these terminals synapse with one muscle fiber (one muscle cell). So, one neuron terminal ends in one muscle cell. This junction between the muscle cell and the motor neuron terminal is called Neuromuscular junction. As you see in the picture this is an example of neuromuscular junction: The parts of neuromuscular junction: Note that the specialized part of the muscle cell which the terminal ends in is the motor end plate so the terminal synapses with specialized part of the muscle cell not the whole muscle cell. The purpose of action potential generated in the motor neuron is to release the neurotransmitters which are Acetylcholine So once acetylcholine is released it will increase the concentration in the synaptic cleft. So 2 P a g e -The membrane of the muscle is called sarcolemma -Nerve terminal ends into a small invaginated part of the muscle membrane called synaptic gutter which is the motor end plate -At the bottom of synaptic gutter, muscle membrane has small folds called subneural clefts, which increase the surface area of synaptic gutter. -The small space (20-30nm) between the terminal and muscle membrane, where the neurotransmitter is released to stimulate muscle, is called synaptic cleft (synaptic space).
as increase in concentration, acetylcholine has increase probability to bind to its receptors on the sarcolemma. These receptors are linked to Na+ channels so the type of channels which are activated by binding of acetylcholine to its receptors are chemical gated Na+ channels (note why chemical gated channels? Because they are activated in response to chemical substance which is acetylcholine) So, what is the outcome? The outcome is small depolarization potentials which are sub threshold potential and called Motor End Plate Potentials (MEPPs). (you should remember that this is similar to EPSPs that in the synapse at the level between neurons). Now, the summation of these MEPPs leads to reach the threshold and by reaching the threshold, the voltage gated Na+ channels at the periphery of the muscle cell are active and result in generation of action potential. Now, the action potential spread toward the whole sarcolemma of the muscle cell. Remember: we also have acetylcholine esterase enzyme in the neuromuscular junction which purpose to limit and keep the concentration of acetylcholine in very minimal amount in the synaptic cleft by destroying it to prevent frequent excitations of the muscle cell. There are some pathological problems related to the transmission of action potential to the muscle cell: for example, myasthenia gravis which is an autoimmune disease in which the body form antibodies against Na chemical gated channels of the motor end plate and that lead to destruction of these channels and inhibition of transmission of action potential to the muscle cell and end in paralysis. However, we can increase the transmission of action potential to the patient with myasthenia gravis by giving acetylcholine esterase inhibitors ex (neostigmine or physostigmine) because they increase the concentration of acetylcholine in the cleft and therefore increase the chance of acetylcholine to bind to its receptors and more channels activated. By that we make the situation better than before and increasing the probability of generation action potential in the level of muscle cell. In addition, we can make the situation better by another way which is putting substance that do the same function of acetylcholine that can activate the receptors. Transmission can also fail by inhibition of acetylcholine receptors by curariform drugs such as D-tubocurarine, which can affect transmission of impulse from the nerve terminal to the muscle membrane by blocking the action of Ach on its receptor So, we study two situations in which there is inhibition of transmission of action potential: 1) Patient with myasthenia gravis due to destruction of sodium gated channels 2) Inhibition of acetylcholine receptors by the drugs mentioned above. 3 P a g e
Remember again not the whole sarcolemma is specialized but the only specialized area is the motor end plate which forms the neuromuscular junction with the terminal of the motor neuron. And again, each one muscle cell synapse with one terminal so, only one neuromuscular junction for each one muscle cell. Note: the type of channels in motor end plate is chemical gated Na channels but at the periphery is voltage gated Na+ channels. Example similar to that is that the cell body of the neuron has more concentration of chemical gated channels but at the axon and axon hillock there are more concentration of voltage gated channels Now, we end the process of transmission of action potential from the bottom terminal to the muscle cell that generated at the periphery of the muscle cell and spread all over the muscle cell. So, how does the contraction process happen? FIRST, at the surface of muscle membrane, there are small openings for tubules that run deeply (in transverse direction) in the muscle cell known as transverse tubules (Ttubules). These tubules contain extracellular fluid due to the opening that connects with the extracellular fluids. Also, they are membranous structures and their membrane is similar to the sarcolemma and they are located at the junction between the A band and I band. They also contain voltage gated sodium channels that transmit the action potential that reach it from this opening at the sarcolemma. So, the action potential is transmitted deeply inside the muscle cell. In addition, we have sacs at the sides of T tubule and these sacs belong to the sarcoplasmic reticulum which contains Ca++. And the action potential that generated in these T tubules will cause the release of Ca++ NOTE: the release of Ca++ is NOT due to depolarization of sarcoplasmic reticulum, it is absolutely WRONG, but will discuss in the next points There is a protein which joins the two membranes together (the sarcoplasmic reticulum & T tubule) which called Foot protein but still we have small space between the two membranes 4 P a g e
This foot protein has two parts; one part which is embedded in the transverse tubule and called dihydropyridine receptor and the other part which is embedded in the sarcoplasmic reticulum and work as Ca++ channel and called ryanodine receptor. As you see in the picture, this is the structure of foot protein: Dihydropyridine receptors works as sensor of voltage, so depolarization happens in the T tubule will be sensed by the foot protein and results in conformational change of the whole foot protein. The ryanodine receptor which works as Ca++ channel and embedded in the sarcoplasmic reticulum will open and results in the release of Ca++ in the sarcoplasm So, as you know the increasing in Ca++ concentration by 1000-fold in the sarcoplasm will result in binding of Ca++ to the Troponin c and the whole contractile process will happen. Side Note: These receptors (dihydropyridine and ryanodine) are called this so because dihydropyridine and ryanodine can bind to the dihydropyridine receptors and ryanodine receptors respectively, however we do not have either of the two chemical compounds in the human body (not produced but can be obtained from external sources like plants). But suppose they are found in the body they will result in conformational change and releasing of calcium without action potential. However, in our body we cannot get contraction of skeletal muscles without action potential. 5 P a g e
Note that the only source for Ca++ in contraction process is not from the outside but from the sarcoplasmic reticulum. So, what do you expect to be find in someone who has hypocalcemia? It will result in muscle spasm (tetanus)! Why? Remember we said previously the most post synaptic potentials are IPSPs and the calcium will be needed to release the inhibitory neurotransmitters from the vesicles in the presynaptic terminals. So, by that we result in less inhibition and then more chance for excitation "by why? It s supposed to have less contraction since the concentration of calcium is less so it is not to bind to troponin c!!, remember that the Ca++ that used in the contraction process is from the sarcoplasmic reticulum and the calcium that used in the presynaptic terminal inters via the presynaptic membrane channels from the outside. In addition, Patients with alkalosis may develop tetanus. why? Because the calcium ions become in less ionic form and what we need actually is in the ionic form so result in tetanus. At the membrane of sarcoplasmic reticulum, there are also highly active Ca++ pumps. These pumps concentrate Ca++ inside the sarcoplasmic reticulum by 10.000 folds (Ca++ concentration in sarcoplasmic reticulum = 10-3 molar, in the sarcoplasm during rest = 10-7 molar, and during excitation of muscle = 2X10-4 molar). The rapid uptake of Ca++ by these active pumps results in muscle relaxation. So, we end the first concept which is Excitation-Contraction process. The picture below summarizes this process: 6 P a g e
Smooth muscles: We want to talk generally about smooth muscle because we want to discuss it in details in the GI system. Smooth muscle cells are widely distributed in our body so we can find them in uterus, blood vessels, GI tract, and urinary tract and so on. Unlike skeletal muscles, smooth muscles are involuntarily controlled by different mechanisms. As you see, this is a smooth muscle cell in the relaxed (left) and contractile (right) forms. You notice that there is a difference in structure between smooth muscle cell and what previously studied in skeletal muscle cell Smooth muscle cell contains contractile proteins as skeletal muscle cells but the arrangement is different; they are not striated as skeletal muscle cell. Note the globular proteins which are called dense bodies which are like the Z line in skeletal muscle cell as they hold thin filaments Note the lines here which refer to the thin and thick filaments (actin & myosin) So, when smooth muscle cell gets contracted, the distance between the two dense bodies shortens. Remember the function of these dense bodies is similar to Z lines As you see, the organization of these contractile proteins doesn t form cylinders as in skeletal muscle cell Also, it is not approved up to now that smooth muscle cells do have neuromuscular junction as in skeletal muscle cell. what happens in smooth muscle cell is that a terminal synapses with the whole smooth muscle cell not (there is no specialized region (end plate) as in skeletal muscle) Then, the terminal releases its neurotransmitters in the cleft and interacts with the membrane receptors of the smooth muscle cell. we can have both types of receptors (excitatory receptors or inhibitory receptors) and they are not found in specialized region as in skeletal muscle cell (motor end plate) but on the WHOLE muscle cell. Now, the excitatory receptors can cause contraction and the inhibitory receptors can cause 7 P a g e
relaxation We said that there are many types of control of smooth muscles, one of them is the chemical control: When the neurotransmitters bind to the excitatory receptors, it will activate an enzyme which is called phospholipase c (PLC) PLC will degrade phospholipids which results in the formation of IPS and DAG. IP3 causes the release of Ca++ from the intracellular store that causes muscle contraction. Note that the smooth muscle cell can form action potential too but the action potential varies between the different smooth muscle cells according to the location (in the uterus, blood vessel, etc.) and this action potential activates Ca++ channels in the sarcolemma and the calcium inters the cell from outside. So, we have two resources of calcium in smooth muscle cells (from S.R that is chemically activated & from outside (ECM) via voltage activated channels) CONCLUSION, the contractile process in smooth muscle cell depends on the release of calcium from outside to inside and also from the sarcoplasmic reticulum (Both ways can happen). BUT in the skeletal muscle only and only from the sarcoplasmic reticulum Now, the increase of Ca++ will result in binding of Ca++ to calmodulin. Once we have Ca++- calmodulin complex. This will activate an enzyme which is (MLCK) Myosin Kinase and this kinase phosphorylate the heads of myosin result in increasing affinity between the myosin and actin and result in contraction. 8 P a g e
for relaxation, there is another enzyme which is phosphatase that dephosphorylates the myosin heads and decrease the affinity between the actin and myosin that results in relaxation. The relaxation in smooth muscle cells also involves a decrease in Ca++ concentration by increased activity of Ca++ pumps located at the plasma membrane and sarcoplasmic reticular membrane. The doctor said also that there is another mechanism of inhibition that results in relaxation which is done by c AMP produced by adenylyl cyclase Remember: in skeletal muscle the heads of myosin are already phosphorylated but the problem was in hiding the binding sites of actin by tropomyosin. 9 P a g e
This table shows you the differences between the different types of muscle cells: Don t forget to refer to the handout أع د ترميم نفس ك... واغ ر س قدم ك يف األرض إ ك ن سي د مشوار ك! 10 P a g e