Receptors & Synaptic Integration

2 Main Classes of Neurotransmitters

Glutamatergic (Ionotropic)

Cholinergic

1) small molecules

2) peptides – large proteins

ACh

biogenic amines

amino acids

Dale's Principle: neuron has only 1 transmitter (WRONG)

co-transmitters – more than one transmitter can b present in neuron

neuropeptides = secretory granules

small molecules = synaptic vesicles

Henry Dale classified neurons by transmitter

Criteria

1) must b synthesized & stored in presynaptic neuron

2) rmust be released by presynaptic axon

3) experimentally – must mimic postsynaptic effect on presynaptic stimulation

demonstrates receptors activated on postsynaptic cell

Choline acetyltranferase (ChAT) – enzyme manufactured in soma & transferred to terminal

vesicular ACh transporter – transport ACh into vesicle

acetylcholinesterase AChE – manufacture by cholinergic neuron & secreted into synaptic cleft

choline transporter – transports choline into presynaptic terminal (recycle)

combines choline & Acetyl CoA to form acetylchline

Myesthenia Gravis

autoimmune disease against ACh

treatment: anticholineterases

weakness & fatigue of voluntary muscles

Nicotinic recptor = ionotropic

Muscarinic = metabotropic

receptors

Kainate

coexistence of NMDA & AMPA

NMDA

AMPA

ions

both ligand & voltage gated

Ca2+

Na+

K+

ligand: glutamate must bind

voltage: at rest Vm channel is blocked by Mg2+

Mg2+ block removed by depolarization

(+) ion repelled by relatively positive charge inside cell

opening = activity dependent

AMPA channels mediate initial depolarization (Na+ & K+)

reason why AMPA & NMDA coexist

coincidence detector

channels open only when presynaptic & postsynaptic cell = active

Na+ & Ca2+ enter postsynaptic cell

presynaptic = releasing glutamate

postsynaptic = depolarized (thanks to AMPA) so Mg2+ block removed from NMDA receptor channel

increased Ca2+ causes cascade of events

activate enzymes

Na+

K+

regulates opening of ion channels

affect gene expression

increased synaptic strength for memory & learning

GABAergic

GABA-A = Cl- channel

Inhibitory (IPSP)

Glycine = Cl-

G-Protein Coupled Receptors (Metabotropic)

not ion channels

modify ion channels & other targets

exert effects through GTP-binding proteins

long-lasting effects compared to ionotropic

involved in neuromodulation

G-protein = trimetric w/ 3 subunits – alpha, beta, gamma

Process

amplify signal

when alpha subunit binds GDP complex = inactive

when transmitter binds GPRC, GDP becomes GTP & complex splits in active alpha & beta-gamma subunits

alpha & beta-gamma interact w/ ion channels/enzymes that activate 2nd messengers

hydrolysis of GTP by the alpha-subunit reassembles inactivate trimer

Direct Action ("short pathway")

Indirect (2nd Messenger Cascade)

effector is ion channel

i.e. muscarinic AChR

effector is enzyme

i.e. beta NE receptor

protein kinase = key downstream enzyme

transfer phosphate from ATP in cytosol to proteins (phosphorylation)

phosphorylation changes conformation of protein & dictates opening/closing

protein phosphatases – remove phosphates from protein (dephosphorylation)

Synaptic Integration

sensory input –> CNS –> motor output

integration = relationship between inputs & outputs

Divergence: most cells send inputs to several other neurons

Convergence: most cells receive inputs from several cells

Central synapses

@ NMJ AP in presynaptic cell WILL lead to EPP in muscle cells large enough to reach threshold

in CNS presynaptic neuron is unlikely to excite postsynaptic cell to threshold

EPSP & IPSP work simultaneously on cell

integration of (+) & (-) inputs occurs on dendrites & soma

synapses add together in 2 ways

spatial summation

temporal summation

many inputs from several presynaptic cells lead to depolarization to threshold

one presynaptic cell sends sequential inputs that lead to depolarization to threshold

subthreshold signal decay w/ distance

location of inhibitory inputs

presynaptic inhibition

postsynaptic inhibition

decrease amount of depolarization in terminal

less quanta released

specific – aimed @ particular excitatory inputs

non-specific

affects all inputs

shunting inhibition

inhibitory synapse closer to soma than excitatory

causes outward current

shunts signal through Cl- channel opening