receptors bind specific ligands

Receptors Bind Specific Ligands

Common ligands for receptors include ….. hormones – alter target cell metabolic behavior neurotransmitters – lead to action potential of neuron

Signal Transduction

Neuron schematic

axon

myelin sheath

dendrites

nerve endings nt release

nt receptors Cell body

synapse

Membranes are electrically polarized

Ion Channels in Nerve Signaling

Molecular Components of Nerve Transmission

Acetylcholine: neurotransmitterAcetylcholine Receptor

choline acetyltransferse : enzyme

Na+/K+ ATPase (Pump) : TransporterAcetylcholine Esterase : enzyme

Na+ voltage-gated channelK+ channel – (efflux)

Signal Transmission in Nerve Cells

Synapse (50nm): ACh diffusion

Along Cell : depolarisation very rapid

Synapse Area

ACh

Na+

ACh

Na+

Na+A + Ch

Nerve Transmission Chronology Nerve cell depolarised (stimulus)

Releases ACh into next synapse 10nM 300 mM in 1ms

ACh binds AChR a2bgd

Na+ channel opens - depolarisation.opens voltage gated Na+ channels & action potential

Na+/K+ pump removes Na+

ACh-esterase destroys ACh

The Acetylcholine Receptor• Nicotinic acetylcholine receptor:

– Ion channel for influx of Na+, Ca2+

– Gate opened by acetylcholine

AChR

AChRa2bgd

268,000 MW

O + ||

(CH3)3 – N - CH2 - CH2 – O – C – CH3

acetylcholine

closed form

open formLL LLL

S

S

SS

S

ACh

ACh

L

LL

LL

SSS

SS

ACh

ACh

ACh binding to AChR Ka = 108 M-1s-1

binding time = 100 ms closed open = 30 ms stays open ~ 1ms impulse rate ~ 1000 s-1

Acetylcholine Esterase kcat = 25,000 s-1

KM = 12.5 mM kcat/KM = 2 x 108 M-1s-1

Acetylcholine

Acetylcholine esterase

O ||CH3-C-O-CH2-CH2-N-(CH3)3

+

O ||CH3-C-O- + HO-CH2-CH2-N-(CH3)3

+

ACh binding to AChR

• Blocked by snake venom proteins• Curare has same effect• Antibodies in Myasthenia Gravis• Result is Paralysis• Tetrodotoxin blocks Na+ channel

Bungarotoxin (a snake venom)

Binding to segment of AChR (red)

Acetylcholine Esterase InhibitorsParathion: insecticideSarin: Nerve Gas

As Alzheimer’s MedicationHuperazine A: plant alkaloid & Chinese folk medicine

Aricept (Donepezil)