neuropharm

neurotransmitter

drug or ligand

Dynamic

relationship between a neurotransmitter and its receptor

Clinical actions of drugs affect…

neuronal plasticity: activation of drugs affects the neurons, and these neurons adapt or change over time to better respond to the drug.

Allosteric modulator

drug that binds to a receptor at a different site from the active site (will always be non-competitive)

Affinity

expressed as Kd (concentration at which half the receptors have been bound to the ligand).

Lower Kd = ?

higher affinity

Bmax

maximum amount of binding (should see a plateau here)

Potency

Measures the necessary amount of drug to produce an effect of a given magnitude

Lower Kd = higher affinity = ?

higher potency

Efficacy

actual biological effect of the drug (not its interaction with other things). It is independent of affinity.  

Agonists

drug that imitates the effect of the endogenous ligand (not same efficacy, but same effect) 

Antagonists

molecule that could be competitive or not. Binds to the receptor of the endogenous ligand and is inert. Does not allow the effect to happen (blocking).  

3 types of g-protein coupled receptors

Gs, Gi/o, Gq

Gs?

stimulate cAMP levels when coupled with neurotransmitters via activation of adenylyl cyclase (AC), which synthesizes cAMP

Gs -> AC -> cAMP -> ion channels/PKA (PKA -> 3^rd messengers -> biological responses) 

Gs

Gi/o 

Gi -| AC -| cAMP -| no opening of ion channels

Inhibit voltage gated Ca2+ channels

Gi/o

Gq 

Neurotransmitter binds -> Gq (coupled with the PLC) -> PI -> IP3 binds -> ER to increase intracellular calcium stores.

Amino Acids

building blocks of proteins (nts) involved in normal metabolism 

Glutamate 

Primary excitatory nt

GABA 

Primary inhibitory nt

Glutamate (synthesis)

in presynaptic terminal in the brain from glucose and other precursors

glutamate Degradation/Recycling

EEAT1/2 and the Na+ and H+ dependent pump system called N-1 (SN1) 

glutamate receptors

ionotropic and metabatropic

ionotropic glutamate receptors

NMDA/AMPA/kainate

NMDA/AMPA/kainate receptors

binding to these receptors -> open postsynaptic cation channels (Na+ > Ca2+) 

NMDA receptors depend on ….

AMPA receptors (on their quick depolarization)

NMDA receptors have…

a Mg+ block in a potential more negative than –50 mV, which blocks the movement of ions in the extracellular fluid (even in the presence of glutamate).

the Mg+ block is released when….

the membrane potential depolarizes (becomes more positive). Requires binding of 2 different agonists (glutamate and glycine – termed co-agonists) 

AMPA and kainate receptors…

desensitize within milliseconds of exposure (because they’re so short acting) to agonists

Kainate receptors

are cation-selective ligand gated ion channels. Found in presynaptic terminals in both inhibitory and excitatory synapses where they can both facilitate or depress nt release. 

what is the canonical kainate receptor pathway

ionotropic – membrane depolarization -> transmitter release

what is the non-cononical kainate receptor pathway

metabotropic – membrane excitability -> transmitter release

mGluRs

Glutamate receptors

3 groups of mGluRs

mGluR1&5, 2&3, 4/5-8

MGlu1 and mGlu5

reduce cell excitability overall, are found on postsynaptic neurons adjacent to excitatory synapses 

mGluRs 1&5 are bound to…

Gq 

mGluRs 1&5 do what?

Inhibit L-type voltage-gated Ca2+ channels and N-type Ca2+ channels. Activation can close voltage-gated K+ channels, resulting in a slow depolarization and neuronal excitation.

MGlu2 and mGlu3 are bound to what?

Gi/o

mGluR4, 6-8 

Found on presynaptic terminals where they modulate transmitter release. Lead to the blockade of both excitatory glutamatergic and inhibitory GABAergic synaptic transmission. Can also inhibit voltage-gated Ca2+ channels on the presynaptic nerve terminal membrane (act as autoreceptors).  

GABAa

ionotropic (opens Cl- channel – hyperpolarizes cell)

GABAb

metabatropic (GPCR subtype)

GABAb are linked to what?

Gi/o linked receptors (inhibit Ca2+ by inhibiting AC which inhibits cAMP, open K+ channels to re/hyperpolarize) 

GABAb are located:

on both pre and post synaptic membranes. Pre: can function as auto receptors and inhibit further GABA release. Or can just inhibit release of glutamate. 

Monoamine degradation occurs how

catabolized by monoamine oxidase (MAO)

Acetylcholine

Regulator of sleep-wake cycle and of arousal and attention-related behaviors - motion. 

ACh synthesis

Synthesized in terminals and mitochondria in a reversible reaction by the enzyme choline acetyltransferase (ChAT).

ACh degradation

Enzyme Acetylcholinesterase (AChE) hydrolyzes ACh into acetate and choline.  

ACh receptors

muscarininc and nicotinic

Muscarinic receptors

GPCRs

Muscarinic receptors types

2 types: M1, 3, 5 & M2, 4

muscarinic receptors M1, 3, 5

couple Gq

M2, 4:

couple Gi 

muscarinic m2 and 4 act as …

autoreceptors to control ACh synthesis and release.

Nicotinic receptors (nAChRs)

ligand-gated channels

Nicotinic receptors (nAChRs) function:

activation by ACh leads to rapid influx of Na+ and Ca2+ -> depolarization -> rapid desensitization.  

Orexin receptors

Orexin A and B: produced in the lateral hypothalamic area (LPH) and PH. Bind to 2 receptors (OX1 and OX2)

orexin OX1 is coupled with

Gq

orexin OX2 is coupled with

Gi/o (sometimes Gq)

3 catecholamines

DA, NE, Epinephrine

catecholamine synthesis

all synthesized from the AA tyrosine

catecholamine rate limiting enzyme

tyrosine hydroxylase (TH)

catecholamine degradation

reuptake into presynaptic terminals via neurotransmitter-specific transporters. Metabolized by catechol-O-methyltransferase (COMT) (not histamine or 5-HT) 

Dopamine transported by

vesicular monoamine transporter protein 2 (VMAT2).  

DA transporter

DAT moves nts from the synaptic cleft into the cytoplasm of the presynaptic terminal, where it is loaded into vesicles by VMAT2 or degraded by MAO 

DA receptors are

G-coupled

DA D1

D1 (D1 and D5) receptors: coupled to Gs or Golf. 

DA D2

D2 (D2-D4) receptors: coupled to Gi/o. 

• D2 and D3 function as presynaptic auto-receptors and as postsynaptic receptors 

Norepinephrine (NE) located…

locus coeruleus contains 50% of all NE neurons

NE transported by

vesicular monoamine transporter protein 2 (VMAT2)

NE transporter

NE transporter (NET) moves nts from the synaptic cleft into the cytoplasm of the presynaptic terminal, where it is loaded into vesicles by VMAT2 or degraded by MAO 

NE receptors are

g-coupled

NE receptor NE alpha:  

• NE alpha:  

• A1: Gq coupled 

• A2: Gi coupled; function as inhibitory auto-receptors and as postsynaptic receptors 

NE receptor beta

• NE beta: 

• Gs coupled 

5-Ht synthesized by

AA tryptophan – so it has similar anatomic organization as catecholamines

5-HT Rate limiting enzyme

Rate limiting enzyme: tryptophan hydroxylase (TPH)

5-HT transported by

VMAT2

5-HT transporter

5-HT transporter (SERT) moves nts from the synaptic cleft into the cytoplasm of the presynaptic terminal, where it is loaded into vesicles by VMAT2 or degraded by MAO 

how many know recpetors of 5-Ht are there?

15!

14 5-Ht receptors are

GPCRs

1 5-HT receptor is

ionotropic

5-HT1A, B, D receptors

are somatodendritic autoreceptors at cell bodies and dendrites; activation reduces cell firing, so inhibits synthesis and release of 5-HT. Highly homologous.

5-HT1A, B, D receptors couple…

Signal by coupling Gi.  

The 5-HT3 receptor is

ionotropic: activation of this receptor opens a non-selective cation channel and triggers rapid depolarizing current that is carried by Na+ and K+.  

histamine is synthesized

Produced in one step by decarboxylation of the amino acid histidine decarboxylase. Synthesized exclusively by neurons in the TMN that lies in the posterior hypothalamus (HP).  

histamine receptors

are all gpcrs

histamine receptors H1

couple to Gq 

histamine receptors H2

couple to Gs. 

histamine receptor H3

couple to Gi and act as an inhibitory autoreceptor and as a heteroreceptor (receptor regulating the synthesis and/or release of mediators other than its own ligand).  

neuropeptides

short proteins that serve as nts. Generally, it binds to G protein-linked receptors (slower acting).

neuropeptides location

Found w/in the CNS and the Periphery in both sympathetic and parasympathetic nervous system. Some are released directly into the blood and act as hormones (oxytocin and vasopressin). Others act as hormones secreted by endocrine glands (luteinizing hormone). Others act w/in the peripheral organs such as the digestive system (cholecystokinin). 

neuropeptide synthesis

requires transcription of DNA into RNA (mRNA) and translation from mRNA to protein.  

neuropeptide receptors

g-protein linked receptors at synapses, axons, cell bodies, and dendrites.  Receptors undergo internalization after sustained binding to a ligand. These are then recycled to the plasma membrane or degraded.  Neuropeptides don’t really cross the BBB. 

Neuropeptides are stored in…

large dense core vesicles (LDVCs), assembled in the Golgi and then transported to the synapse. 

Small nts are stored in ….

small clear synaptic vesicles (SSVs) that are assembled in the synaptic terminals.  

SSVs release nts in response to …

large transient (single APs) increases in intracellular Ca2+. Under short term activity. Nts are released in synapses and those that don't bind are cleared by transporters (like DAT) or enzymes (acetylcholinesterase). 

LDCVs: release peptides due to…

increases in Ca2+ of lesser magnitude but longer duration (trains of APs; longer Ca2+ diffusion). Under sustained activity.

Opioid receptor subtypes: 

three: mu, kappa, delta

opiod mu receptor

bind B endorphins here & morphine like opiates  

• Concentrated in regions associated with descending analgesic pathways and in reward related pathways. 

opiod kappa receptor

autoreceptors. Dynorphins bind here