A naturally occurring amino acid substitution in the voltage-dependent sodium channel selectivity filter affects channel gating

2013 ◽  
Vol 199 (10) ◽  
pp. 829-842 ◽  
Author(s):  
Mingming Wu ◽  
Na Ye ◽  
Biswa Sengupta ◽  
Harold H. Zakon
2003 ◽  
Vol 9 (1) ◽  
pp. 55-64 ◽  
Author(s):  
M Okada ◽  
J K Northup ◽  
N Ozaki ◽  
J T Russell ◽  
M Linnoila ◽  
...  

1998 ◽  
Vol 111 (3) ◽  
pp. 421-439 ◽  
Author(s):  
Catherine J. Smith-Maxwell ◽  
Jennifer L. Ledwell ◽  
Richard W. Aldrich

Substitution of the S4 of Shaw into Shaker alters cooperativity in channel activation by slowing a cooperative transition late in the activation pathway. To determine the amino acids responsible for the functional changes in Shaw S4, we created several mutants by substituting amino acids from Shaw S4 into Shaker. The S4 amino acid sequences of Shaker and Shaw S4 differ at 11 positions. Simultaneous substitution of just three noncharged residues from Shaw S4 into Shaker (V369I, I372L, S376T; ILT) reproduces the kinetic and voltage-dependent properties of Shaw S4 channel activation. These substitutions cause very small changes in the structural and chemical properties of the amino acid side chains. In contrast, substituting the positively charged basic residues in the S4 of Shaker with neutral or negative residues from the S4 of Shaw S4 does not reproduce the shallow voltage dependence or other properties of Shaw S4 opening. Macroscopic ionic currents for ILT could be fit by modifying a single set of transitions in a model for Shaker channel gating (Zagotta, W.N., T. Hoshi, and R.W. Aldrich. 1994. J. Gen. Physiol. 103:321–362). Changing the rate and voltage dependence of a final cooperative step in activation successfully reproduces the kinetic, steady state, and voltage-dependent properties of ILT ionic currents. Consistent with the model, ILT gating currents activate at negative voltages where the channel does not open and, at more positive voltages, they precede the ionic currents, confirming the existence of voltage-dependent transitions between closed states in the activation pathway. Of the three substitutions in ILT, the I372L substitution is primarily responsible for the changes in cooperativity and voltage dependence. These results suggest that noncharged residues in the S4 play a crucial role in Shaker potassium channel gating and that small steric changes in these residues can lead to large changes in cooperativity within the channel protein.


2012 ◽  
Vol 102 (3) ◽  
pp. 327a
Author(s):  
Deborah Capes ◽  
Manoel Arcisio-Miranda ◽  
Brian Jarecki ◽  
Robert French ◽  
Baron Chanda

1996 ◽  
Vol 271 (27) ◽  
pp. 16035-16039 ◽  
Author(s):  
Adrian Etter ◽  
Doris F. Cully ◽  
James M. Schaeffer ◽  
Ken K. Liu ◽  
Joseph P. Arena

2010 ◽  
Vol 52 (4) ◽  
pp. 377-382 ◽  
Author(s):  
Marcelino Aguirre ◽  
Adriana E. Flores ◽  
Genoveva Álvarez ◽  
Alberto Molina ◽  
Iram Rodriguez ◽  
...  

2010 ◽  
Vol 299 (5) ◽  
pp. C1203-C1211 ◽  
Author(s):  
Kai Guo ◽  
Xianming Wang ◽  
Guofeng Gao ◽  
Congxin Huang ◽  
Keith S. Elmslie ◽  
...  

We have found that phospholemman (PLM) associates with and modulates the gating of cardiac L-type calcium channels (Wang et al., Biophys J 98: 1149–1159, 2010). The short 17 amino acid extracellular NH2-terminal domain of PLM contains a highly conserved PFTYD sequence that defines it as a member of the FXYD family of ion transport regulators. Although we have learned a great deal about PLM-dependent changes in calcium channel gating, little is known regarding the molecular mechanisms underlying the observed changes. Therefore, we investigated the role of the PFTYD segment in the modulation of cardiac calcium channels by individually replacing Pro-8, Phe-9, Thr-10, Tyr-11, and Asp-12 with alanine (P8A, F9A, T10A, Y11A, D12A). In addition, Asp-12 was changed to lysine (D12K) and cysteine (D12C). As expected, wild-type PLM significantly slows channel activation and deactivation and enhances voltage-dependent inactivation (VDI). We were surprised to find that amino acid substitutions at Thr-10 and Asp-12 significantly enhanced the ability of PLM to modulate CaV1.2 gating. T10A exhibited a twofold enhancement of PLM-induced slowing of activation, whereas D12K and D12C dramatically enhanced PLM-induced increase of VDI. The PLM-induced slowing of channel closing was abrogated by D12A and D12C, whereas D12K and T10A failed to impact this effect. These studies demonstrate that the PFXYD motif is not necessary for the association of PLM with CaV1.2. Instead, since altering the chemical and/or physical properties of the PFXYD segment alters the relative magnitudes of opposing PLM-induced effects on CaV1.2 channel gating, PLM appears to play an important role in fine tuning the gating kinetics of cardiac calcium channels and likely plays an important role in shaping the cardiac action potential and regulating Ca2+ dynamics in the heart.


2017 ◽  
Vol 10 (1) ◽  
Author(s):  
Catherine E. Vrentas ◽  
Justin J. Greenlee ◽  
Gregory H. Foster ◽  
James West ◽  
Marianna M. Jahnke ◽  
...  

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