Lecture 11: Intro to autonomics Flashcards
1
Q
Adrenergic Fibers exceptions
A
- The sympathetic fibers supplying the sweat glands release acetylcholine.
- The adrenal medulla releases epinephrine and norepinephrine.
- Dopamine is released by some sympathetic fibers.
- Renal vascular smooth muscle
2
Q
Innervation by ANS
A
- Most organs are innervated by both divisions of the ANS.
- In the heart, the parasympathetic predominates.
- The control of blood pressure is mainly sympathetic.
3
Q
Cholinergic transmission
A
Acetylcholine is synthesized in the cytoplasm from acetyl-CoA and choline, a reaction catalyzed by choline acetyltransferase (ChAT).
Acetyl CoA is synthesized in mitochondria. Choline is transported from the extracellular fluid into the neuron terminal by a sodium-dependent carrier (CHT1). The uptake of choline by this transporter is the rate-limiting step for the synthesis of ACh.
ACh is transported from the cytoplasm into vesicles by means of a carrier protein on the vesicle membrane called the vesicular ACh transporter (VAChT). VAChT is an antiporter that couples an influx of ACh with an efflux of H+.
4
Q
Adrenergic transmssion
A
- Tyrosine is transported across the blood-brain barrier into the adrenergic neuron. Tyrosine (like other neutral amino acids such as phenylalanine and leucine) is transported by system L across the blood brain barrier in a Na+-independent manner.
- Once tyrosine gains entry into the neuron the rate-limiting step in dopamine synthesis is the conversion of tyrosine to L-dihydroxyphenylalanine (L-DOPA) by the enzyme TH
- DOPA is subsequently converted to dopamine by aromatic L-amino acid decarboxylase (DOPA decarboxylase).
- Vesicular monoamine transporter (VMAT) translocates dopamine into synaptic vesicles in exchange for H+. In adrenergic neurons, intravesicular dopamine-β- hydroxylase converts dopamine to norepinephrine. Norepinephrine is then stored in the vesicle until release.
- In adrenal medullary cells, norepinephrine returns to the cytosol, where phenylethanolamine N-methyltransferase (PNMT) converts norepinephrine to epinephrine. Epinephrine is then transported back into the vesicle for storage.
- Release of the transmitter is similar to the calcium-dependent process described for cholinergic terminals.
- In addition to norepinephrine, ATP, dopamine-β-hydroxylase and certain peptide cotransmitters are also released into the cleft.
- Norepinephrine and epinephrine can be metabolized:
- COMT:2 forms of COMT:soluble cytosolic form and a membrane bound form which is anchored to the RER. COMT catalyses the transfer of a methyl group from S-adenosylmethionine to a -OH of the catechol. COMT is found in nearly all cells, including erythrocytes; thus, the enzyme can act on extraneuronal catecholamines.
- MAO:located on outer membrane of mitochondria,and expressed in most neurons. MAO oxidatively deaminates monoamines to their corresponding aldehydes; these can be converted, in turn, by aldehyde dehydrogenase to acids or by aldehyde reductase to glycols. There are two isozymes of MAO: MAO-A and MAO-B. The two isozymes have some degree of substrate specificity: MAO-A preferentially deaminates norepinephrine, epinephrine and serotonin. MAO- B deaminates dopamine more rapidly than serotonin and norepinephrine. MAO in the GI tract and liver plays an important protective role by preventing access to the general circulation of ingested, indirectly acting amines, such as tyramine and phenylethylamine, that are contained in food.
- Metabolism is not the primary mechanism for termination of action of norepinephrine physiologically released. Termination results from simple diffusion away from the receptor site and reuptake into the nerve terminal or into perisynaptic glia or smooth muscle cells.
- Reuptake of norepinephrine into the nerve terminal is mediated by the Na+-dependent norepinephrine transporter (NET) (also called uptake 1).
- Indirectly-acting sympathomimetics (e.g., tyramine and amphetamines) can be taken up into noradrenergic nerve endings by uptake 1, and displace norepinephrine from storage vesicles.
5
Q
Subtypes of muscarinic receptors
A
- M1 receptors. Found mainly on CNS and autonomic ganglia. They mediate excitatory effects.
- M2 receptors. Found in heart, and on presynaptic terminals of peripheral and central neurons. They are inhibitory, mainly by opening K+ channels and by inhibiting Ca2+ channels. M2 receptor activation is responsible for vagal inhibition of the heart, as well as presynaptic inhibition in the CNS and periphery.
- M3 receptors. Located in smooth muscle and secretory glands. Mainly excitatory: they mediate stimulation of glandular secretions (salivary, bronchial, sweat) and contraction of visceral smooth muscle.
6
Q
The Endothelial M3 Receptor
A
- No innervation of the vasculature by the parasympathetic system exists.
- There are uninnervated M3 receptors on the endothelial cells that line blood vessels.
- Activation of endothelial M3 receptors leads to a rise in intracellular calcium.
- Calcium activates NO synthase,leading to formation of NO.
- NO diffuses from the endothelial cells into the adjacent smooth muscle cells in the blood vessel wall.
- In the cytosol of the smooth muscle cell, NO activates guanylyl cyclase, which catalyzes formation of cGMP from GTP.
- cGMP activates cGMP-dependent protein kinase, which phosphorylates proteins leading to relaxation of the smooth muscle wall, resulting in vasodilation.
7
Q
Molecular basis of muscarinic transmission
A
- M1, M3 activate Gq
- M2 interacts with Gi
8
Q
β-Adrenergic Receptors subtypes
A
3 subtypes of βreceptors: β1 and β2 and β3.
- Theyaredefinedbytheiraffinitiesfor epinephrine and norepinephrine.
- β1 & β3 have approximately equal affinity for epinephrine and norepinephrine
- β2 have higher affinity for epinephrine than for norepinephrine.
All β-adrenergic receptors stimulate adenylyl cyclase via interaction with Gs.
9
Q
Beta-adrenergic-induced effects
A
- Activation of hepatic glycogen phosphorylase (β2 effect), the enzyme that catalyzes the rate-limiting step in glycogenolysis. Protein kinase A catalyzes phosphorylation of phosphorylase kinase, thereby activating it. Phosphorylase kinase then phosphorylates and activates phosphorylase. Protein kinase A also catalyzes phosphorylation and inactivation of glycogen synthase; this effect decreases the rate of glycogen synthesis.
- Activation of TAG lipase in adipose tissue, leading to release of free fatty acids (β3 effect). The lipase is activated when it is phosphorylated by protein kinase A.
- β2-adrenergic receptor activation promotes relaxation of smooth muscle. The mechanism involves phosphorylation of myosin light chain kinase to an inactive form.
- In the heart, stimulation of β1-adrenergic receptors leads to positive inotropic and chronotropic responses.
- Norepinephrine stimulates renin secretion by a direct action on the juxtaglomerular cells of the kidney. This effect is mediated by β1-adrenergic receptors.
10
Q
alpha-adrenergic effects
A
α1-Adrenergic Receptors
- Present in postsynaptic membrane of effector organs.
- Activation of α1-adrenergic receptors leads to activation of phospholipase C through activation of Gq. Hydrolysis of PIP2 results in generation of diacylglycerol (DAG) and IP3. IP3 stimulates release of Ca2+ from intracellular stores via a specific receptor-mediated process, while DAG is an activator of protein kinase C.
- In most smooth muscles, the increased concentrations of intracellular Ca2+ cause contraction as a result of activation of the calmodulin-dependent myosin light chain kinase. In contrast, the increased concentrations of intracellular Ca2+ that result form stimulation of α1-adrenergic receptors in GI smooth muscle cause hyperpolarization and relaxation by activation of Ca2+-dependent K+ channels.
α2-adrenergic receptors
- Located on presynaptic nerve endings, reducing norepinephrine release; and postsynaptically on other cells, such as the β cell of the pancreas, reducing insulin release. α2 adrenergic receptors couple to a variety of effectors.
- α2 adrenergic receptors inhibit adenylyl cyclase activity (via Gi) and cause intracellular cAMP levels to decrease. α2 adrenergic receptors also activate K+ channels, resulting in membrane hyperpolarization.
- α2 adrenergic receptors evoke vasoconstriction by opening voltage-gated Ca2+ channels.
11
Q
Dopamine receptor effects
A
Note: focus on relaxation of smooth muscle of renal vascular bed
12
Q
Tissues controlled by the ANS in the eye
A
13
Q
PRESYNAPTIC MODULATION OF ACh RELEASE
A
In addition to presynaptic α2 adrenergic receptors, other inhibitory heteroreceptors on cholinergic terminals include A1, H3, and opioid receptors.
14
Q
Integration of cardiovascular function
A
However, the negative feedback baroreceptor response to increased mean arterial pressure causes decreased sympathetic outflow to the heart.
As a result, the net effect of norepinephrine is
- To increase peripheral vascular resistance
- To cause a moderate increase in mean arterial pressure
- Reflex bradycardia after vasoconstriction (the opposite of the drug’s direct action).
15
Q
Presynaptic Regulation of Norepinephrine Release
A
- Numerous heteroreceptors on sympathetic nerve terminals also inhibit norepinephrine release; these include M2, 5-HT, PGE2, histamine, enkephalin, and DA receptors.
- Enhancement of sympathetic neurotransmitter release can be evoked by activation of presynaptic facilitatory β2 adrenergic receptors and angiotensin II receptors.
17
Q
Pharmacology of the eye
A
