TY - JOUR
T1 - Structural mechanisms of assembly, permeation, gating, and pharmacology of native human rod CNG channel
AU - Xue, Jing
AU - Han, Yan
AU - Zeng, Weizhong
AU - Jiang, Youxing
N1 - Publisher Copyright:
© 2021 Elsevier Inc.
PY - 2022/1/5
Y1 - 2022/1/5
N2 - Mammalian cyclic nucleotide-gated (CNG) channels are nonselective cation channels activated by cGMP or cAMP and play essential roles in the signal transduction of the visual and olfactory sensory systems. CNGA1, the principal component of the CNG channel from rod photoreceptors, can by itself form a functional homotetrameric channel and has been used as the model system in the majority of rod CNG studies. However, the native rod CNG functions as a heterotetramer consisting of three A1 and one B1 subunits and exhibits different functional properties than the CNGA1 homomer. Here we present the functional analysis of human rod CNGA1/B1 heterotetramer and its cryo-EM structures in apo, cGMP-bound, cAMP-bound, and L-cis-Diltiazem-blocked states. These structures, with resolution ranging from 2.6 to 3.3 Å, elucidate the structural mechanisms underlying the 3:1 subunit stoichiometry, the asymmetrical gating upon cGMP activation, and the unique pharmacological property of the native rod CNG channel.
AB - Mammalian cyclic nucleotide-gated (CNG) channels are nonselective cation channels activated by cGMP or cAMP and play essential roles in the signal transduction of the visual and olfactory sensory systems. CNGA1, the principal component of the CNG channel from rod photoreceptors, can by itself form a functional homotetrameric channel and has been used as the model system in the majority of rod CNG studies. However, the native rod CNG functions as a heterotetramer consisting of three A1 and one B1 subunits and exhibits different functional properties than the CNGA1 homomer. Here we present the functional analysis of human rod CNGA1/B1 heterotetramer and its cryo-EM structures in apo, cGMP-bound, cAMP-bound, and L-cis-Diltiazem-blocked states. These structures, with resolution ranging from 2.6 to 3.3 Å, elucidate the structural mechanisms underlying the 3:1 subunit stoichiometry, the asymmetrical gating upon cGMP activation, and the unique pharmacological property of the native rod CNG channel.
KW - CNGA1 and CNGB1 heterotetramer
KW - cGMP and cAMP activation
KW - cyclic nucleotide-gated
KW - native rod CNG channel
KW - signal transduction
KW - visual and olfactory sensory system
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U2 - 10.1016/j.neuron.2021.10.006
DO - 10.1016/j.neuron.2021.10.006
M3 - Article
C2 - 34699778
AN - SCOPUS:85121694844
SN - 0896-6273
VL - 110
SP - 86-95.e5
JO - Neuron
JF - Neuron
IS - 1
ER -