Chapter 49 The Neuromuscular Junction and Muscle Contraction 1

2 Propagation of an action potential along an axon. In myelinated nerves, clusters of sodium ion channels can be millimeters apart from each other.

3 Chemical Synapse NT is released by exocytosis Post-release of the NT -it can be destroyed by enzymes (acetylcholinesterase) -taken up by the nerve terminal that released it (reuptake) -taken up by surrounding glial cells.

4 Transmitter-gated ion channels 1)Concentrated in the region of the synapse. 2)Open momentarily allowing brief permeability to the ion. 3)The more NT released the longer the gates are opened. 4)The resulting action potential can only be triggered only if the membrane potential increases enough to open a sufficient number of voltage- gated cation channels.

5 Neuromuscular Junction in a Frog -single axon on a skeletal muscle cell.

The Acetylcholine Receptors at the Neuromuscular Junction Are Transmitter-gated Cation Channels. Between a motor neuron and a skeletal muscle Ach receptor gene was the first ion channel gene to be cloned and sequenced. Only ligand-gated channel whose 3-D structure has been determined. Receptor is made of 5 transmembrane polypeptides Encoded by 4 separated genes The 4 genes are very similar in sequence implying they evolved from a single ancestral gene. 2 Ach molecules bind to the complex and opens the channel. Acetylcholinesterase. If Ach persists for too long as a result of excessive nerve stimulation, the channel inactivates. 6

7 Three conformations of the Ach receptor

8 Structural Model for the Ach Receptor Closed State: blocked by hydrophobic side chains of 5 leucines Negatively charged side chains at the ends of the pore ensure that only cations (mainly sodium, potassium with some calcium) will pass through the channel. Influx of sodium ions leads to membrane depolarization and muscle contraction.

9 NM Transmission Involves 5 Different Sets of Ion Channels.

Molecular Motors Motor Proteins Use energy from repeated ATP hydrolysis to move. Lots of different motor proteins in eukaryotic cells. They carry “cargo” (organelles), or they cause cytoskeleton filaments to slide against each other such as in muscle contraction, ciliary beating and cell division. Basic Makeup Head Region or motor domain: binds and hydrolyzes ATP. 10

Myosin II: 2 heavy chains and 4 light chains 2 heavy chains form a dimer driven by the attraction of the hydrophobic amino acids of these heavy chains. 11

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When ATP was added, the actin filaments began to glide along the surface. 13

A myofibril is often as long as the muscle cell itself. Sarcomere 14

15 Skeletal Muscle Myofibrils

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17 The Sliding-Filament Model of Muscle Contraction The myosin heads are described as “walking” toward the attached ends of the actin filaments.

18 Accessory Proteins of Muscle Contraction Titin: acts as a molecular spring to keep the myosin in the middle of the sarcomere and allows the muscle fiber to recover after being overstretched. Nebulin: acts as a molecular ruler to determine the length of the filament. It is an actin-binding protein. Cap Z: anchors the plus end of the actin to the Z disc. Tropomodulin: caps the minus end of the actin to prevent it from depolymerizing.

22 T tubules and the sarcoplasmic reticulum

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24 Increase in calcium ion concentration is fast (passed within milliseconds) and momentary because the calcium ions are pumped back into the SR thus allowing the myofibrils to relax. Role of ATP: filament sliding and pumping of calcium ions

25 Muscle Contraction AnimationAnother Animation

26 A subtle mutation in cardiac myosin can cause familial hypertrophic cardiomyopathy. Different forms of cardiac muscle myosin and cardiac muscle actin are expressed in the heart.. And changes that would not cause noticeable consequences in other tissues cause serious heart problems.

27 Familial hypertrophic cardiomyopathy is a frequent cause of sudden death in young athletes. Condition: heart enlargement, abnormally small coronary vessels and cardiac arrhythmias.

28 40 point mutations in genes encoding for cardiac myosin heavy chains almost all causing changes in or near the motor domain of the myosin as well as a dozen in other genes coding for contractile proteins such as the myosin light chains, cardiac troponin and tropomyosin have been found that cause the disease.