Abstract
Given the association of a ?2 mutation (R43Q) with epilepsy and the
reduced cell surface expression of mutant receptors, we investigated a
role for this residue in a1ß2?2 receptor assembly when present in each
subunit. Regardless of which subunit contained the mutation, mutant GABAA
receptors assembled poorly into functional cell surface receptors. The
low level of functional expression gives rise to reduced GABA EC50s
(a1(R43Q)ß2?2 and a1ß2(R43Q)?2) or reduced benzodiazepine potentiation
of GABA-evoked currents (a1ß2?2(R43Q)). We determined that a 15-residue
peptide surrounding R43 is capable of subunit binding, with a profile
that reflected the orientation of subunits in the pentameric receptor.
Subunit binding is perturbed when the R43Q mutation is present
suggesting that this residue is critical for the formation of
inter-subunit contacts at (+) interfaces of GABAA subunits.
Rather than being excluded from receptors, ?2(R43Q) may form
non-productive subunit interactions leading to a dominant negative
effect on other receptor subtypes.
| Original language | English |
|---|---|
| Pages (from-to) | 120-127 |
| Number of pages | 8 |
| Journal | Molecular and Cellular Neuroscience |
| Volume | 29 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 2005 |
Cite this
}
The epilepsy mutation, γ2(R43Q) disrupts a highly conserved inter-subunit contact site, perturbing the biogenesis of GABAA receptors. / Hales, Timothy G.; Tang, Haiyan; Bollan, Karen A.; Johnson, Sara J.; King, Dale P.; McDonald, Neil A.; Cheng, Aixin; Connolly, Christopher N.
In: Molecular and Cellular Neuroscience, Vol. 29, No. 1, 2005, p. 120-127.Research output: Contribution to journal › Article
TY - JOUR
T1 - The epilepsy mutation, γ2(R43Q) disrupts a highly conserved inter-subunit contact site, perturbing the biogenesis of GABAA receptors
AU - Hales, Timothy G.
AU - Tang, Haiyan
AU - Bollan, Karen A.
AU - Johnson, Sara J.
AU - King, Dale P.
AU - McDonald, Neil A.
AU - Cheng, Aixin
AU - Connolly, Christopher N.
PY - 2005
Y1 - 2005
N2 - Given the association of a ?2 mutation (R43Q) with epilepsy and the reduced cell surface expression of mutant receptors, we investigated a role for this residue in a1ß2?2 receptor assembly when present in each subunit. Regardless of which subunit contained the mutation, mutant GABAA receptors assembled poorly into functional cell surface receptors. The low level of functional expression gives rise to reduced GABA EC50s (a1(R43Q)ß2?2 and a1ß2(R43Q)?2) or reduced benzodiazepine potentiation of GABA-evoked currents (a1ß2?2(R43Q)). We determined that a 15-residue peptide surrounding R43 is capable of subunit binding, with a profile that reflected the orientation of subunits in the pentameric receptor. Subunit binding is perturbed when the R43Q mutation is present suggesting that this residue is critical for the formation of inter-subunit contacts at (+) interfaces of GABAA subunits. Rather than being excluded from receptors, ?2(R43Q) may form non-productive subunit interactions leading to a dominant negative effect on other receptor subtypes.
AB - Given the association of a ?2 mutation (R43Q) with epilepsy and the reduced cell surface expression of mutant receptors, we investigated a role for this residue in a1ß2?2 receptor assembly when present in each subunit. Regardless of which subunit contained the mutation, mutant GABAA receptors assembled poorly into functional cell surface receptors. The low level of functional expression gives rise to reduced GABA EC50s (a1(R43Q)ß2?2 and a1ß2(R43Q)?2) or reduced benzodiazepine potentiation of GABA-evoked currents (a1ß2?2(R43Q)). We determined that a 15-residue peptide surrounding R43 is capable of subunit binding, with a profile that reflected the orientation of subunits in the pentameric receptor. Subunit binding is perturbed when the R43Q mutation is present suggesting that this residue is critical for the formation of inter-subunit contacts at (+) interfaces of GABAA subunits. Rather than being excluded from receptors, ?2(R43Q) may form non-productive subunit interactions leading to a dominant negative effect on other receptor subtypes.
U2 - 10.1016/j.mcn.2005.01.002
DO - 10.1016/j.mcn.2005.01.002
M3 - Article
C2 - 15866052
VL - 29
SP - 120
EP - 127
JO - Molecular and Cellular Neuroscience
JF - Molecular and Cellular Neuroscience
SN - 1044-7431
IS - 1
ER -