Part 2: drugs affecting cholinergic transmission
H1: Cholinergic transmission
Synaptic transmission is the communication language in CNS and PNS
2 parts
• Electrical component: carried by AP
• Chemical component
Electrical component
AP: transmembrane voltage in mV as a function of time (sec). 3 parts TEKENING
→ 1st part: depolarization phase. Ion channels selective for Na will permeate through the mbr. Ion
channels will open. Na C is much bigger on outside. Electrochemical force will be inward, so Na
comes in. Mbr voltage will become less negative. No E required.
→ 2nd phase: repolarization phase. Carried by K ions. C K is bigger intracellularly. K ion channels will
open and permeate K along the C gradient. More + ions leave so mbr voltage becomes negative
again. No E required.
→ 3rd phase: hyperpolarization phase. More + ions left so mbr voltage becomes negative again. More
than resting mbr potential.
As a result of each AP net influx of Na+ → needs to get back out: intrinsic mbr protein that pumps out
Na and K in. Requires E (ATP) → Na-K-pump or Na-K-ATPase.
AP propagates along the nerve terminal until it reaches its terminus
→ chemical component takes over.
Vesicles loaded with NT will fuse with the presynaptic mbr = process that involves Ca and SNARE
proteins. The NT are released into the synaptic cleft, diffuse through it and then bind on postsynaptic
receptors where AP is generated.
Interplay between chemical and electrical component.
Important slide: subdivision of nervous system.
H1: drugs on peripheral nervous system (right)
Later chapters: drugs on the CNS (left).
CNS is also divided into parts of the PNS.
PNS: efferent, OS, PS.
BBB = collection of tissues and BV that forms a
physical barrier for the permeation of drugs into
the CNS. Very lipophilic boundary (so drugs that
have a very lipophilic character).
Efferent somatic system:
Neurons that originate from the CNS make a synaps with the muscle. Specific NT: nAch.
,OS:
Neurons that make a synaps with BV. NT: NA (noradrenaline). Specific NT: mAch.
PS:
Targets salivary glands. Specific NT: mAch.
Ach receptors:
• Activation by nicotine
• Activation by muscarine
Choline: 4ary nitrogen, means that
NT is permanently + charged
→ relatively polar mol.
Ach = synthesized under influence
of CAT (choline acetyl transferase):
enzyme that transfers an acetyl
group onto choline (one step
synthesis).
→ choline converted into Ach
→ Ach concentrated into vesicles
→ will be released in synaptic cleft
when AP reaches its terminus
Very important that NT is eliminated from the synapse otherwise the postsynapt R will stay occupied
by the NT
→ desensitization (unresponsive to new pulse of Ach)
→ specific enzyme for Ach on postsyn mbr: acetylcholinesterase
→ does the reverse reaction of CAT
→ choline recycled to a choline carrier = transport protein
nAchR: pentamer with central pore in mbr
→ selective for cations
→ ligand gated ion channel
→ ligand binding site located at interphases between each
subunit (5 interphases)
→ binding causes conformational change that opens pore
→ permeates cations
→ creates AP
→ excitatory ligand gated receptor
mAchR: GPCR → 7 transmembrane domains
Funnel shape where the muscarine or NT are bound
→ 1 single binding site (itt 5 in nAchR)
→ Rely on intracell G proteins for their signal transduction
→ Couples to Gi (inhibitory) protein
→ End result of signaling of mAch leads to decrease of C of cAMP
,Ach binds to mAchR
→ conformation change
→ activation Gi protein (orange = alfa subunit, blue = beta, green = gamma)
→ GDP will be released and replaced by GTP
→ complex will dissociate into alfa and b-g subunit. Alfa targets adenylylcyclase (synthesizes cAMP)
→ decrease cAMP concentration
Gq → q means that R signals through IP3 and Ca2+ (not
cAMP)
Muscle type: heteropentameric.
→ You need all 5 different subtypes for it to be
functional
Class II: most abundant subtypes in the brain: alfa 7
homopentameric receptor
Class III: heteropentameric
, Negative chronotropic
effect: decrease of heart
rate due to decrease of
AP firing
Negative dromotropic
effect: decrease of heart
rate due to decrease of
AP firing by pacemaker
cells in the AV node
Disease in which patients raise Ab against their own
muscle nicotinic R.
L: Fab fragment of Ab of patient.
Fab region of an Ab = Ag binding region.
Ab attacks a very specific region in alfa subunit of
muscle type R: MIR = Main Immunogenic Region.
Binding of Ab to alfa subunit will make R dysfunctional
→ main symptom = muscle weakness
→ drugs that activate nAchR
H1: Cholinergic transmission
Synaptic transmission is the communication language in CNS and PNS
2 parts
• Electrical component: carried by AP
• Chemical component
Electrical component
AP: transmembrane voltage in mV as a function of time (sec). 3 parts TEKENING
→ 1st part: depolarization phase. Ion channels selective for Na will permeate through the mbr. Ion
channels will open. Na C is much bigger on outside. Electrochemical force will be inward, so Na
comes in. Mbr voltage will become less negative. No E required.
→ 2nd phase: repolarization phase. Carried by K ions. C K is bigger intracellularly. K ion channels will
open and permeate K along the C gradient. More + ions leave so mbr voltage becomes negative
again. No E required.
→ 3rd phase: hyperpolarization phase. More + ions left so mbr voltage becomes negative again. More
than resting mbr potential.
As a result of each AP net influx of Na+ → needs to get back out: intrinsic mbr protein that pumps out
Na and K in. Requires E (ATP) → Na-K-pump or Na-K-ATPase.
AP propagates along the nerve terminal until it reaches its terminus
→ chemical component takes over.
Vesicles loaded with NT will fuse with the presynaptic mbr = process that involves Ca and SNARE
proteins. The NT are released into the synaptic cleft, diffuse through it and then bind on postsynaptic
receptors where AP is generated.
Interplay between chemical and electrical component.
Important slide: subdivision of nervous system.
H1: drugs on peripheral nervous system (right)
Later chapters: drugs on the CNS (left).
CNS is also divided into parts of the PNS.
PNS: efferent, OS, PS.
BBB = collection of tissues and BV that forms a
physical barrier for the permeation of drugs into
the CNS. Very lipophilic boundary (so drugs that
have a very lipophilic character).
Efferent somatic system:
Neurons that originate from the CNS make a synaps with the muscle. Specific NT: nAch.
,OS:
Neurons that make a synaps with BV. NT: NA (noradrenaline). Specific NT: mAch.
PS:
Targets salivary glands. Specific NT: mAch.
Ach receptors:
• Activation by nicotine
• Activation by muscarine
Choline: 4ary nitrogen, means that
NT is permanently + charged
→ relatively polar mol.
Ach = synthesized under influence
of CAT (choline acetyl transferase):
enzyme that transfers an acetyl
group onto choline (one step
synthesis).
→ choline converted into Ach
→ Ach concentrated into vesicles
→ will be released in synaptic cleft
when AP reaches its terminus
Very important that NT is eliminated from the synapse otherwise the postsynapt R will stay occupied
by the NT
→ desensitization (unresponsive to new pulse of Ach)
→ specific enzyme for Ach on postsyn mbr: acetylcholinesterase
→ does the reverse reaction of CAT
→ choline recycled to a choline carrier = transport protein
nAchR: pentamer with central pore in mbr
→ selective for cations
→ ligand gated ion channel
→ ligand binding site located at interphases between each
subunit (5 interphases)
→ binding causes conformational change that opens pore
→ permeates cations
→ creates AP
→ excitatory ligand gated receptor
mAchR: GPCR → 7 transmembrane domains
Funnel shape where the muscarine or NT are bound
→ 1 single binding site (itt 5 in nAchR)
→ Rely on intracell G proteins for their signal transduction
→ Couples to Gi (inhibitory) protein
→ End result of signaling of mAch leads to decrease of C of cAMP
,Ach binds to mAchR
→ conformation change
→ activation Gi protein (orange = alfa subunit, blue = beta, green = gamma)
→ GDP will be released and replaced by GTP
→ complex will dissociate into alfa and b-g subunit. Alfa targets adenylylcyclase (synthesizes cAMP)
→ decrease cAMP concentration
Gq → q means that R signals through IP3 and Ca2+ (not
cAMP)
Muscle type: heteropentameric.
→ You need all 5 different subtypes for it to be
functional
Class II: most abundant subtypes in the brain: alfa 7
homopentameric receptor
Class III: heteropentameric
, Negative chronotropic
effect: decrease of heart
rate due to decrease of
AP firing
Negative dromotropic
effect: decrease of heart
rate due to decrease of
AP firing by pacemaker
cells in the AV node
Disease in which patients raise Ab against their own
muscle nicotinic R.
L: Fab fragment of Ab of patient.
Fab region of an Ab = Ag binding region.
Ab attacks a very specific region in alfa subunit of
muscle type R: MIR = Main Immunogenic Region.
Binding of Ab to alfa subunit will make R dysfunctional
→ main symptom = muscle weakness
→ drugs that activate nAchR
