ANS And GPCR Review Flashcards
What are the targets for the ANS/visceral motor system
- innervates smooth muscle in organs, skin, and body wall
- heart conduction system
- glands in the skin
Compare functions of the SNS with the PSNS on pupils and peristalsis
SNS: “flight or fight”- dilates pupils (mydriasis), slows perstalsis, stims sweat glands, VASOCONSTRICTS most arteries
PSNS: “rest and digest”- constricts pupils (miosis), increased perastalsis
What are some SNS functions?
Increased HR and BP, shunts blood away from skin and viscera to skeletal muscles (vasoconstricts most arteries), bronchial dilation improves oxygenation, dilates pupils, mobilizes stored energy (FA for muscles, glucose for brain), promotes secretion of sweat glands, induces piloerection to conserve heat
What is the difference in SNS and PSNS distribution? Where is dual innervation found?
SNS fibers go EVERYWHERE
PSNS fibers are restricted to plexuses or splanchnic nerves. Go to viscera of thorax abdomen pelvis and head. Not to body wall or limbs.
Organs, major glands, and modified cardiac tissue will have dual innervation
PQ: what effect does the SNS have upon the respiratory tract?
- bronchodilation or constriction
- increased bronchial secretions or decreased
SNS induces bronchodilation to improve oxygenation and reduces secretions to max air exchange
PSNS on lungs constricts bronchi and promotes bronchial secretion
PQ: what is the effect of PSNS on cardiac function?
- increase or decrease rate/strength cardiac contraction
- dilate or constrict coronary arteries
PSNS: decreases HR and contraction, constricts the coronaries at the arteriole level bc not as much need for blood to go out
PQ: what is the effect of SNS on urinary tract?
Contracts internal urethral sphincter and vasoconstricts renal vessels to slow urine production
SNS wants to shunt energy elsewhere, slows urine production and keeps sphincters closed
LO: Compare and contrast the SNS and PSNS in terms of:
1) anatomical location of pre and post ganglionic cell bodies
2) NTs used by pre and post ganglionic neurons
3) receptors expressed in order to carry out target response
1) Both: are two neuron systems from SC/BS to target, presynaptic neurons has cell body in SC or BS
SNS: pre-ganglionic cell bodies in IML grey horn from T1-L2 only, thoracolumbar distribution. T1-6: head, UE, thoracic viscera/foregut. T7-11: body wall, abdominal viscera (midgut). T12-L2: LE, pelvic viscera (hindgut)
Post-ganglionic cell bodies are in the ganglia and send their axons to targeted organs or glands. The sympathetic trunk or paravertebral ganglia runs the entire length of the vertebrae and is the site of synapse for SNS innervating limbs, body wall, thoracic viscera. The pervertebral ganglia is near the abdominal aorta on front of vertebral bodies and is composed of celiac, superior and inferior mesentaric ganglia. It is the site of synapse for SNS innervating abdominal and many pelvic organs
SNS= short, long axons
PSNS: cell bodies for preganglionic are in nuclei of BS (aka cranial nerves) and S2-4. Craniosacral distribution. Cranial- exit as CN III, VII, IX, X. Sacral- exit via anterior roots of spinal nerves S2-4 as pelvic splanchnic nerves.
Postganglionic cell bodies are within the wall (tissue) of the target organ located in an intramural ganglia. Synapse in two places- pelvis or abdomen they are intramural ganglia in wall of organ. Except in head they synapse in COPS ganglia near their targets. Very short. PSNS= Long short
LO: Compare and contrast the SNS and PSNS in terms of:
2) NTs used by pre and post ganglionic neurons
ANS: all preganglionic neurons use Ach as NT
SNS: most SNS post-ganglionic use NE as NT except sweat glands use Ach as post-ganglionic NT
PSNS: Ach is post-ganglionic NT
LO: Compare and contrast the SNS and PSNS in terms of:
3) receptors expressed in order to carry out target response
Adrenergic receptors are used when NE is the NT. Alpha and beta subtypes. Most SNS ike heart and vessels use adrenergic. SNS to sweat glands use cholinergic receptors.
Cholinergic receptors are used when Ach is the NT. Muscarinic/nicotinic cholinergic receptors. PSNS uses cholinergic receptors only
PQ: Where are the synapses for preganglic sympathetics for the body wall, limbs, and thoracic viscera?
In the sympathetic chain ganglia
Body wall, limbs, thorax (heart and lungs) SNS all synapse in SCG
Think about SCG as pregang going to arms and legs and thorax
PQ: Where are the synapses for preganglion sympathetics for the stomach?
Prevertebral ganglion.
Prevertebral ganglion- celiac, superior and inferior mesentaric ganglion. All in abdomen. Abdomen and pelvis= prevertebral ganglion.
LO: Outline the different effects of the SNS on CV, respiratory, urinary, GI systems
SNS:
Cardiovascular system- maintains blood flow to brain, redistributes blood, compensates for blood loss
Regulation of body temperature- regulates blood flow to skin, promotes sweating of skin, induces piloerection
Fight or flight response- increasing HR and BP, shunt blood away from skin and viscera, dilates the bronchi, dilates the pupils, mobilizes stored energy
LO: outline the effects of PSNS on CV, respiratory, urinary, and GI systems.
PSNS: slows the HR
Increases gastric secretion, empties the bowel and bladder
Focuses the eye for near vision- accomodation
Constricts the pupil
Contracts bronchial smooth muscle
Increases peristalsis
PQ: A mid age women with 4 hr hx of severe headache, SCI at C5-6 with catheter, tachycardiac 98 beats/min, dramatic increase in BP. What is the condition and what is mechanism
Acute autonomic dysreflexia. Mechanism: a sensory input from bladder or rectum iniates uncontrolled SNS dischange in patients with SCI above T6. Bladder signal up SC to evoke massive SNS reflex causing widespread vasoconstriction leading to peripheral HTN. Brain detects HTN via baroreceptors then 1) attempts to send inhibition to SNS surge but the descending impulses are unable to travel d/t SCI at T6 or above. 2) the brain tries to bring peripheral BP down by slowing HR via vagus (PSNS) which is intact but can’t fix HTN.
SNS prevails below the level of injury and PSNS prevails above the level of the injury. Once stimulus is removed HTN resolves.
PQ: what CN can detect HTN via baroreceptors in neck?
CN IX and X, glossopharyngeal sends info from carotid sinus to bring BP down
Vagus has baroreceptors in aortic arch to reduce HR and mediate SNS to heart
LO: how do SNS reach their target?
Sympathetics in spinal nerves: innervates smooth muscles and glands of limbs and body wall, use sympathetic chain ganglion aka paravertebral, in thorax and abdomen there is one SNS ganglion per vertebral level.
Cell body in IML, out through ventral root to true spinal nerve, to white ramus (myelinated) into the sympathetic trunk. There the axon can synapse in sympathetic with post synaptic neuron within the same ganglion/level, it can ascend or descend within sympathetic trunk to synapse with another paravertebral ganglion, or pass through without synapsing. After synapsing in sympathetic trunk the axon needs to take off ramp or gray ramus to the dorsal or ventral ramus depending on where the target is. Innervates smooth muscle or glands
Sympathetics to thoracic/hallow organs- use splanchnic nerves to get sympathetics SNS and PSNS to organs. The signal leaves the SC for SNS leave the IML via the ventral roots to sympathetic trunk via white ramus but do not take gray ramus, instead take splanchnic and synapse at a ganglia of plexus- celiac, superior inferior hypogastric
LO: how does PSNS reach their targets?
1) through splanchnic nerves in the sacral region via the anterior roots to sympathetic trunk. Synapse in the intramural ganglion target tissue bc postganglionic cell bodies in the target- long short.
2) in cranial- use CN 3 7 9 10 to synapse in COPS ganglia in intramural ganglion that are CLOSE to target, not in the target like sacral
LO: compare and contract adrenergic and muscarinic receptors effects on cardiac muscle.
Muscarinic receptors: PSNS and Ach, M2 subtype couples with Gi, leads decreased cAMP production by inhibition of adenylyl cyclase, low cAMP lowers intracellular Ca2+, inhibits muscle contraction
Adrenergic receptors: SNS and NE, Beta 1 subtype couples with Gs which stimulates adenylyl cyclase, increased cAMP, increased intracellular Ca2+, Ca binds to troponin, troponin alters relationship of tropomyosin with actin and cardiac muscle contraction results.
What does SNS stimulation lead to in heart muscle
Increased HR via SA node, increased contractility in atria and ventricles, increased conduction velocity in AV node
LO: Differentiate alpha adrenergic receptors from Beta adrenergic receptors in terms of distribution, signaling mechanisms, and organ-specific effects
Distribution: peripheral smooth muscle- alpha receptors dominate and have low affinity for Epi, beta receptors have less fewer in number but increased affinity. Increased Epi triggers both but alpha dominates in flight or fight response, get a contraction in periphery
Skeletal smooth muscle- Beta receptors predominate, in fight or flight response increased epi leads to more beta response in skeletal muscle, leads to vasodilation to skeletal muscles, betas in coronary vessels too
Signaling: alpha1- predominate in general/peripheral circulation smooth muscle arterioles, respond to epi, couple to Gq/11, stims phospholipase IP3, increases inositol triphosphates, increase Ca, stims smooth muscle contraction
Beta1- cardiac muscle, respond to NE, coupled to Gs, stim adenylyl cyclase, increase cAMP, increase Ca, stim cardiac contraction
Beta2- respond to epi, coupled to Gs, stims adenylyl cyclase, increases cAMP, INHIBITS MLCK, causes smooth muscle RELAXATION
predominates in skeletal smooth muscle and airways leading to vasodilation at high SNS input, low distribution high affinity in peripheral circulation- vasodilation with low SNS input
PQ: which G protein, signaling, output would you expect to predominate in airway smooth muscle?
Want vasodilation with SNS input= relaxation
To get vasodilation with SNS input= Beta2
Beta2 coupled protein= Gs
Signaling= Epi, Gs, stim adenylyl cyclase, increase cAMP, inhibit MLCK, smooth muscle relaxation
LO4: why does SNS activation of Beta adrenergic receptors cause cardiac muscle to contract and airway smooth muscle to relax?
Both are driven by epi, same signaling pathway but output in the tissue is different output in the tissue. Cardiac- troponin, smooth muscle of skeletal and airways= MLCK.
Increased cAMP from Gs signaling in Beta1, increases Ca2+, Ca binds to troponin, troponin alters relationship of tropomyosin with actin and cardiac muscle contraction results.
Beta2 increased cAMP from Gs signaling decreases MLCK, leading to relaxation of skeletal and airway smooth muscle- vasodilation
Alpha1 sidenote: output- increase IP3 increase Ca increase MLCK leading to contraction. Since the target is the same you need a different pathway
When the pathway was the same the output was different, if output the same then the pathway is different
Ellis PQ: what class of adrenergic receptors found in detrussor smooth muscle? External sphincter smooth muscle?
Detrussor wants to relax so Beta receptors, want external sphincter to contract- alpha,
Ellis PQ: what is CV effect of alpha blockers?
They cause hypotension becuase they are found on peripheral vascular resistance vessels, block alpha then relax sphincter in bladder and relax peripheral vasculature
What drug is used to treat hyperactive bladder? Mechanism? Target? Does it work?
Mirabegron is used to treat overreactive blader, it is a specific Beta 3 agonist to stimulate relaxation of detrusor muscle. It works but it causes hypertension in some people at higher levels by stimulating beta 1 even though in lab it was B3 specific. Receptor polymorphisms could explain this spillover to Beta1 stimulation
What mechanisms does beta1 increase BP?
Most straightforward is increasing cAMP which increases intracellular Ca2+ stimulating cardiac muscle contraction. Increased cAMP also stimulates juxtaglomerular cells in kidney to release renin. Renin is made to angiotensin I through ACE and then made to II which increases SVR in vasculature.
Describe the mechanism and ligands/receptors that can lead to HTN in peripheral smooth muscle
HTN is from increased contraction and increased vascular resistance of peripheral smooth muscle. All the ligands and receptors he mentioned work through the same signaling pathway (Gq11-IP3-increased Ca-phos MLCK- smooth muscle contraction).
The ligands with receptors are: epi- alpha 1 Angiotensin II- AT1 Endothelin1- ETa Vasopressin- V1
What is the importance of HTN
It can lead to heart failure
Describe the process of HTN leading to heart failure. Is beta agonist helpful?
HTN from SNS input leads to constricted blood vessels= increased work for the heart= chronic stim of SNS to keep up= more epi release.
Chronic stimulation is not the cause of the heart failure- tried Beta agonist and it led to worse heart function
Now know that beta blockers is the preferred treatment to reduce heart function which seems counter intuitive. Discovered that receptors were undergoing desensitization (lose response of receptors to agoinst from chronic stimulation) causing heart failure. This is homologous desensitization from chronic stimulation
What is responsible for desensitization of receptors?
G protein coupled receptor kinases (GRKs). When phosphorylate the receptors then arrestin binds to G alpha protein receptor so G protein cannot bind preventing signaling through G proteins. Receptors bound to arrestin can be degraded or internalized and dephosphorylated and recycled
What is the compensation to HTN leading to heart failure.
With chronic stimulation of receptor the compensation is down regulation of the receptor being desensatized. Points to chronic stimulation being the problem. Why using beta blockers make sense in heart failure and HTN
LO: Describe the distribution of beta receptors in the heart and how that relates to heart failure and therapy
In the heart beta 1 predominate by 70:30 to beta 2. Both beta 1 and 2 at low levels of stimulation increase cAMP. Beta2 with persistent stimulation switches over to Galphai which reduces cAMP. This might be a compensation from chronic stimulation to reduce stimulation.
Beta 1 is subject to desensitization with chronic SNS stimulation. Beta 2 is not. In failing heart the level of beta1 decreases and beta 2 increases 60:40 and activity about 50:50. Beta2 seems to be protective. Might want beta receptors that spare beta2
LO: describe alpha receptors role in the heart normally and when failing heart
Normally alpha 1 receptors are present at about 11%. In failing heart the alpha receptors become relatively more important because of desensitization to beta 1
Alpha 1 works through Gq11 to increase IP3. They are likely pro survival in context of chronic sympathetic stimulation- pro survival, protective to cardiomyocytes
Whereas beta 1 is maladaptive, pro apoptotic to cardiomyocytes, promotes cardiac fibroblasts and fibrosis in context of chronic SNS stimulation
Beta2 is mixed. It starts out Galphas= bad, then Galphai switch is good in context of chronic SNS stimulation.
LO: so wrapping up what in terms of treating HTN leading to heart failure, what targets do you want to hit and which ones do you want to spare?
Beta blockers ideally should be specific to beta 1 and spare beta2 in heart failure. Could use ACE inhibitor to treat HTN leading to heart failure.
Alpha blocker?? It makes sense to block alpha to take away alpha 1 peripheral vasculature contraction and increased BP. But might want to spare alpha receptors for their compensation mechanisms in the heart in heart failure. Clinical trials have shown alpha blockers might not be great in heart failure, lose pro-survival
Can you go back to Ellis’s last slide and name most of the receptors, location, and effects?
Yeah I can do that every now and then.
Heart- Beta 1- contract Kidney- beta 1- renin release Smooth muscle skeletal and airway- beta 2- relax GI tract- beta 2- relax Lens ciliary muscle- beta 2- relax Bladder (detrusor)- beta 3- relax Smooth muscle periphery- alpha 1- contract Bladder sphincter Smooth mm- alpha 1- contract GI tract sphincter - alpha 1- contract Iris radial mm- alpha 1- contract Pilomotor- alpha 1- contract CNS- alpha 2- inhibit NE release
Compare SNS innervation to body wall and limbs to internal organs
Same: start cell bodies in IML T1-L2- out ventral root to spinal nerve
Body wall, limbs, thoracic viscera- to white ramus to SCG, synapse in SCG, axons need to travel and then synapse, take gray ramus to dorsal or ventral ramus to innervate body wall, limbs, or glands
Sympathetics to thoracic organs: take white ramus into SCG, synapse in SCG, take cardiopulmonary sphlanchnic nerve to heart or hallow organs of thoracic viscera
This is correct, ignore flashcards that contradict this
Where are cells bodies for preganlionic PSNS
Nuclei of BS (cranial nerves) or spinal cord S2-4= craniosacral
How do preganglion PSNS travel? for cranial or sacral what nerves are they?
CN: III, VII, IX, X
Sacral: exit anterior roots of S2-4 as pelvic sphlanchnic nerves
Where are postganglionc PSNS cell bodies?
Within wall of tissue of target organ located in intramural ganglion
4 ganglion close to head- COPS
How long are PSNS post ganglionic fibers?
Short because the PSNS cell bodies and synapse point are in the wall of the target organ
What is the tx for autonomic dysreflexia?
Remove inciting stimulus
What effect dominates in arterioles of general circulation in high epi? In low epi?
Alpha 1 receptors are large in numbers, low affinity for epi- will dominate at high epi levels- flight or fight- high epi= contract arterioles of general circulation to redirect blood
Beta 2 receptors are few in number but higher in affinity- will dominate in low epi states, rest and digest- low epi- dilate the arterioles of smooth muscle
How does B2 signal?
Through epi stims B2 receptor to release Gs- stims adenylyl cyclase to increase cAMP which in smooth muscle of general circulation inhibits MLCK- inhibits contraction
What receptor dominates in skeletal muscle smooth muscle circulation? What is the reason and effect?
In skeletal muscle Beta2 is dominate over alpha1
So in flight or fight- increase epi- stim B2- Gs is released- stim adenylyl cyclase- increase cAMP- inhibits MLCK in smooth muscle- smooth muscle relaxes or dilates to allow more blood to fight or flight
Which receptors does Ellis think evolved later?
He this alpha receptors developed later to constrict peripheral vessels during SNS response to allow more blood to skeletal muscle
Why can beta receptors be used as same signaling pathway in both cardiac and smooth muscle
They differ in their output
In cardiac increase cAMP increases Ca - troponin contracts
In smooth muscle- increased cAMP inhibits MLCK to causes smooth muscle relaxation
What if you want to target the same target in smooth muscle but cause different responses?
Need to use different signaling pathway
Ex:
In smooth muscle alpha causes increased IP3 increases Ca increases MLCK==. Contraction
In smooth beta causes increase cAMP which inhibits MLCK= relaxation
What is an effect of beta1 stimulation besides its effect in the heart?
In kidney Beta1 receptor stims Gs- increases cAMP- stims juxtaglomerular cells to release renin and increase SVR through Ang II and increased aldo
