nACh subunit a1 -- Glu 176

Species Original Mutated to Mutation
Human Val 132

Leu

Ile

V132L

V132I

Rat Equivalent Val 107    
Mouse Equivalent Val 107    

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hVal132Leu

When ACh binding was measured, the apparent dissociation constant of the V132L mutant increased five-fold relative to the wildtype. Single channel currents through the mutant were shown to activate in bursts of much shorter duration. The mean duration of the dominant component of the V132L bursts was seven-fold that of the wild-type, and almost identical to that of the patient with myasthenic syndrome. The channel was open for shorter durations with the mutation, thus V132L reduces the probability of channel opening across a range of ACh concentrations.

The curve of the probability of an open channel is shifted to higher concentrations of ACh. This is also seen in a V132I and d V134L, but is most severe in the a V132L mutation.

When mutations in other subunits were studied: b V132L, e V132L and d V134L, only the b and a subunits were shown to have an effect on the kinetics of receptor activation.

Shen XM, Ohno K, Tsujino A, Brengman JM, Gingold M, Sine SM, Engel AG (2003) Mutation Causing Severe Myasthenia Reveals Functional Asymmetry of AChR Signature Cystine Loops in Agonist Binding and Gating Journal of Clinical Investigations 111:497-505

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hVal132Ile

The V132I mutation reduced gating efficiency similar to the V132L mutation, but affects ACh binding to the closed state less than V132L.

Shen XM, Ohno K, Tsujino A, Brengman JM, Gingold M, Sine SM, Engel AG (2003) Mutation Causing Severe Myasthenia Reveals Functional Asymmetry of AChR Signature Cystine Loops in Agonist Binding and Gating Journal of Clinical Investigations 111:497-505

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