1843Claude Bernard (France)

Physiologist

Interested in mechanism by which nerves stimulate the contraction of skeletal muscles

curare

Direct stimulations on Nerves----impulse

Direct stimulations on Muscles----contractionCurare +

Curare + stimulation on nerves → muscles’ contractionX

→Curare somehow acted on the region of contact between the nerve and muscle

1843→1906

John Langley

Physiologist in Cambridge Uni.

Study the ability of nicotine to stimulate the contraction of muscles and the effect of curare in inhibiting nicotine action

→Impulse should not pass from nerve to muscle by an electric discharge, but by the secretion of a special substance on the end of nerve.

“Chemical transmitter” and “receptive substance”

1843→1906→1921Otto Loewi

Physiologist (Austrian-born)

Stimulate the nerve and then transfer the solution to a new heart without vagus, the new heart is inhibited as its own inhibitory nerve have been activated.

→Vagusstoff is acetylcholine(Ach)

1843→1906→1921→1937David Nachmansohn

Neurophysiologist at the Sorbonne

Electric organs of ray are derived from modified skeletal muscle tissue which is rich of acetylcholinesterase (AChase) and nicotinic acetylcholine receptor (nAChR).

Suitable assay to determine the protein

Chen-Yuan Lee and his colleagues

National Taiwan Uni.

1963

α-Bungarotoxin in the venom of a Taiwanese snake

1843→1906→1921→1937→1970s

Isolation of nAChRElectric organs containing the nAChR

Homogenate containing the nAChR

Blend

Centrifuge

Pellet contains membranes fragments

Triton X-100

Affinity chromatography

Purified nAChR

Affinity chromatography

1843→1906→1921→1937→1970s

Structure of nAChRArthur Karlin (Columbia Uni.)

nAChR is a pentamer. It contains 2 copies of α subunit ,and one copy each of β, γ, and Δsubunit.4 different subunits are homologous to one another, each subunit containing 4 homologous transmembrane helices.

1843→1906→1921→1937→1970s

Structure of nAChRJean-Pierre Changeux (Pasteur Instit

ute)

The receptor acts as both a site for binding ACh and a channel for the passage of cations.

The binding of ACh to the receptor caused a conformational change that opened an ion channel within the protein.

1843→1906→1921→1937→1970s→past two decades

Structure of nAChRSequencing, mutation

Electron microscopeMethods

1843→1906→1921→1937→1970s→past two decades

Detailed model of nAChRNigel Unwin and his colleagues

(Medical Research Council of England)

The sequence of events during synaptic transmission with Ach as the

neurotransmitter

Thanks for your listening