1. When you want to move your muscle, your central nervous system sends an electrical signal down nerves to your muscle. At the neuromuscular junction where the nerve and muscle meet, this electrical signal opens up presynaptic voltage-gated calcium channels, causing calcium (Ca) to flow into the nerve terminal. This Ca attaches to synaptotagmin on the presynaptic ACh-containing vesicles, triggering synaptobrevin on the vesicle to intertwine with the syntaxin and SNAP-25 proteins on the cell membrane of the nerve terminal (forming a SNARE complex), tying the vesicle to the cell membrane, causing them to merge, spilling the ACh out of the vesicle and into the synaptic cleft. The amount of acetylcholine (ACh) that each vesicle releases is called a quantumLambert-Eaton Syndrome is due to autoantibodies against the presynaptic voltage-gated calcium channel, causing muscle weakness that improves with repetitive motion. The weakness improves because repetitive motion causes an increase in Ca in the nerve cell, eventually overcoming the blockade of the voltage-gated calcium channels. In Botulism and Botox, the botulinum toxin cleaves the SNAP-25, preventing the ACh-containing vesicles from merging with the plasma membrane of the nerve terminal, preventing muscle from contracting. Botox paralysis the muscles in your face, alleviating wrinkles.
  2. Two ACh bind to each nicotinic acetylcholine receptor (cation-selective), causing it to open, allowing all ions to pass through (although Na predominates). This causes a depolarization known as Excitatory Postsynaptic Potential (EPSP)Myasthenia Gravis is caused by autoantibodies against these nicotinic ACh receptors, causing muscle weakness that worsens with repetitive motion.
  3. Unlike the rest of the post-synaptic muscle cell membrane (aka sarcolemma), the immediate post-synaptic membrane is not excitable (to cause action potential). Thus the EPSPs need to build up large enough to travel to the adjacent sarcoplasm surfaces that are excitable. Then with enough depolarization that reaches action potential threshold, the voltage-gated sodium channels in the adjacent surfaces open, then in an all-or-nothing manner, an action potential is triggered.
  4. Meanwhile, the ACh that is left in the synaptic cleft diffuse, get chewed up by acetylcholinesterases (and choline get reuptaken).Myasthenia gravis is treated with acetylcholinesterase inhibitors, which blocks ACh from being chewed up, increasing the amount of ACh in the synaptic cleft, overcoming the autoantibodies that block the nicotinic ACh receptors. Insecticides and poisons such as sarin are also acetylcholinesterase inhibitors, both causing your (or the bug’s) muscles to be perpetually contracted.
  5. Meanwhile, the Lateral Sacs of the Sarcoplasmic Reticulum (SR) are storing calcium that are weakly and temporarily bound to Calsequestrin found in the lateral sacs. The calcium in the sarcoplasm keeps getting uptaken by the longitudinal portion of the SR and gets transported to the lateral sacs for storage. Two lateral sacs flank the sides of each T-tubule (long invaginations of the sarcolemma) in a triad manner.
  6. As the action potential reach the T-tubules, it triggers the L-type Ca channels in the T tubule to mechanically trigger the opening of the lateral sac Ca-release channels (aka Ryanodine Channels, Ca-induced Ca channels). Although extracellular calcium may come through the L-type Ca channels into the muscle cell, it is not the cause of the opening of the Ryanodine channels nor are they significant in terms of providing the Ca needed for muscle contraction (which mainly gets the calcium from the SR through the Ryanodine channels). The drug Dantrolene treats Malignant Hyperthermia by antagonizing Ryanodine receptors on the Ryanodine channel.
  7. The lateral sac Ca-release channel open to release Ca out of the SR. The Ca binds to Troponin C of the Troponin Complex attached to the tropomyosin of the actin filament (collectively called thin filament). The attachment causes the tropomyosin to shift on the actin filament, revealing the active site on the actin filament where the myosin head of the thick filament can attach.
  8. As the Calcium is released from the lateral sacs, it also stimulates the longitudinal portion of the SR to uptake more Ca.
  9. In addition to Ca binding to Troponin on the thin filament, ATP must also attach and be hydrolized on the myosin head of the thick filament for the cross-bridge cycle to happen, causing muscle contraction. Here is the Cross-bridge Cycle:
    ATP attachment = crossbridge detachment.
    ATP Hydrolysis = crossbridge stroke and attachment
    ADP falling off = POWER STROKE!!
    Rigor mortis is due to lack of ATP, preventing the myosin head from detaching from the actin filament. Ca also cannot be pumped back into the lateral sacs, and so Ca accumulates and saturates the troponin, causing permanent contraction.

Resting force = preload = “stretched rubber band force,” so the more you stretch, the larger the resting force or preload. The more connective tissue a muscle has the more difficult it can stretch.

Q: What causes tetanus?
A: when you keep stimulating muscles to the point that more Ca is released than reabsorbed to the lateral sacs.

Q: What determines the maximum tetanus level?
A: the number of cross bridges available for contraction.

Q: Why can you not tetanize cardiac muscle?
A: Because you’ll die. Also because calcium takes longer to migrate through longitudinal SR to get to lateral sacs. The refractory period is also too long.

Q: Describe the load-velocity relationship.
A: Increase load, decrease velocity of shortening, and decrease shortening length. Vmax is the maximum velocity with no load. Isometric total force is heaviest load without velocity. Vmax reflects the intrinsic rate at which myosin ATPase can split ATP.


  1. Cardiac Muscle actually has real calcium-stimulated calcium-release channels, as opposed to the mechanically linked channels in skeletal muscle. In cardiac muscle, L-type Ca channel is indirectly (not mechanically) linked with Ryanodine receptor.
  2. In addition to lateral sacs (which are not as regular as in skeletal muscle), cardiac muscle also has subsarcolemmal sacs to store Ca. Despite the name, they are NOT continuous with Sarcolemma.
  3. As more calcium enter from extracellular spaces into the cardiac myocyte, more calcium can be reuptaken and stored in the lateral sacs → serve as an inotropic reserve for the heart.
  4. Ca2+ leaves a cardiac myocyte through sarcolemmal channels by several mechanisms. A Na+-Ca2+ exchange is one mechanism. Digoxin (drug that makes heart beat harder) – blocks sodium/potassium pump → sodium gradient not maintained → calcium cannot be pumped out → more calcium stay bound to TnC → heart beats harder.
  5. Mitochondria play a role in buffering cyoplasmic Ca2+. Since Mitochondria can also reuptake Calcium, it acts as a buffer for calcium levels in the cardiac muscle cell. It also has a Na/Ca exchanger, with Ca coming into the mitochondria. The intracellular sodium concentration gradient needs to be maintained via a Na/H+ exchanger. Of course, all this H+ outside the mitochondria also helps it produce ATP.
  6. Catecholamines → faster reuptake of calcium by longitudinal bands → faster relaxation of heart → faster beating.
  7. Changes in force or shortening due to more available internal Ca2+ are termed an increase in inotropism or contractility.

One definition of inotropism or contractility is a change in active force development in the absence of a change in preload or resting muscle length.

Q: Why does increasing number of action potentials increase force development in cardiac muscle?
A: Because when you increase number of Na coming in, you reduce the Ca/Na exchange (Na in, Ca out). More calcium will stay in cell, and cause more inotropy and more force per beat.
Preload does not affect Vmax in Cardiac Muscle. Catecholamines do (but does not change resting force-length relationship)


  1. Smooth Muscle = same force, but more shortening, less energy consumed, less velocity of shortening than skeletal or cardiac muscle.
  2. Visceral Smooth Muscle – Stretch Activated → Ca channels open → myosin regulatory light chain phosphorylation
  3. Multiunit Smooth Muscle – Graded Voltage (Local Depolarization) Activated (caused by neurotransmitters) → Ca channels open → myosin regulatory light chain phosphorylation
  4. Smooth muscle does not require extracellular Calcium. Either by neurotransmitter (Ach,Norepi) or hormone (endothelin)-induced production of IP3 in multiunit smooth muscle or stretch-activation in visceral smooth muscle, Ca channels in SR can open, causing calcium to influx in, binding to Calmodulin, which phosphorylates myosin kinase, which phosphorylates calponin (inhibitory) to fall of regulatory light chain on myosin. Myosin can then bind actin and cause contraction. Myosin phosphatase is needed to dephosphorylate the light chain myosin, and so this is why Smooth muscle contracts slower.

Nicotinic = ionotropic, blocked by curare
Muscarinic = metabotropic, blocked by atropine



Hypertension – Propranalol, Phentolamine (side effects – shunt to cardiac), Calcium Channel Blocker
Hypotension — Epinephrine
Angina Pectoris – Propranalol, Nitroglycerine (produces NO)
Raynaud’s Disease — Phentolamine
Anaesthesia Adjunct– alpha-adrenergic agent (AAA for AA), cocaine
Diarrhea – muscarinic receptor blocker (atropine) (stops parasympathetic/bowel movement), opioids

Irritable Bowel Sydrome – Serotonin antagonist or Serotonin reuptake blockers


Glaucoma: 2 Causes:
Closed Angle = aqueous humor can’t drain → drill hole in iris or use cholinergic agent (parasympathetic,
to constrict pupils)
Open Angle = canal of schlemm blocked → aqueous humor can’t drain → treat with beta-receptor
blocker (sympathetic blocker, since sympathetic secretes aqueous humor). But since
sympathetic also contracts levator palpebrae and orbicularis oculi (so you look “shocked”), you’ll have ptosis and sunken eyeballs with this treatment.

Parasympathetic: Cilliary contraction (rounder lens, see near)
Sympathetic: Dilates pupil, Secrete Aqueous Humor (so you look “shocked”)

Basically, you should encourage parasympathetic or stop sympathetic with Glaucoma patients.


Parasympathetic: watery salivary secretion
Sympathetic: thick salivary secretion, sweating (only palms and soles are adrenergic, all others ACh), goose bumps

Remember Hands and Soles are adrenergic. Rest of body is Cholinergic for sweating.
Sweaty palms patients need beta-adrenergic blocker. A cholinergic would have elevated body temperature to a lethal degree!!
Remember: Beta-Adrenergic blocker NOT Cholinergic blocker!!!

HORNER’S SYNDROME – When sympathetic nerve is blocked
S = stellate ganglion
S = superior cervical ganglion
S = sunken eyeball
P = Ptosis
A = Anhydrosis
M = Miosis
And other sympathetic-block symptoms.


Allergy → histamine released → Laryngeal muscle swell → so you also sound very high-pitched with an allergic reaction! → treat with beta-adrenergic drug or epinephrine → increase sympathetic (remember bronchiole constriction is parasympathetic)

ASTHMA – use parasympathetic blocker or beta-adrenergic agent (NOT blocker)

URINARY INCONTINENCE — That’s why you want to pee (relaxed detrusor) when you are startled, but you can’t (closing of internal sphincter). Treat with sympathetic blocker.

ERECTILE DYSFUNCTION — Viagra –> inhibits Nitric Oxide destruction (released by ACh)

Increase preload, increase velocity of shortening, increase force, same time, same Vmax
Increase afterload, decrease velocity of shortening
Increase inotropy, increase velocity of shortening, increase force, shorten time, increased Vmax