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The Journal of Neuroscience, January 10, 2007, 27(2):270-278; doi:10.1523/JNEUROSCI.3801-06.2007

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Cellular/Molecular
Slow Conformational Changes of the Voltage Sensor during the Mode Shift in Hyperpolarization-Activated Cyclic-Nucleotide-Gated Channels

Andrew Bruening-Wright and H. Peter Larsson

Neurological Sciences Institute, Oregon Health and Science University, Beaverton, Oregon 97006

Correspondence should be addressed to H. Peter Larsson, Neurological Sciences Institute, Oregon Health & Science University, 505 N.W. 185th Avenue, Beaverton, OR 97006. Email: larssonp{at}ohsu.edu

Hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels are activated by hyperpolarizations that cause inward movements of the positive charges in the fourth transmembrane domain (S4), which triggers channel opening. If HCN channels are held open for prolonged times (>50 ms), HCN channels undergo a mode shift, which in sea urchin (spHCN) channels induces a >50 mV shift in the midpoint of activation. The mechanism underlying the mode shift is unknown. The mode shift could be attributable to conformational changes in the pore domain that stabilize the open state of the channel, which would indirectly shift the voltage dependence of the channel, or attributable to conformational changes in the voltage-sensing domain that stabilize the inward position of S4, thereby directly shifting the voltage dependence of the channel. We used voltage-clamp fluorometry to detect S4 movements and to correlate S4 movements to the different activation steps in spHCN channels. We here show that fluorophores attached to S4 report on fluorescence changes during the mode shift, demonstrating that the mode shift is not simply attributable to a stabilization of the pore domain but that S4 undergoes conformational changes during the mode shift. We propose a model in which the mode shift is attributable to a slow, lateral movement in S4 that is triggered by the initial S4 gating-charge movement and channel opening. The mode shift gives rise to a short-term, activity-dependent memory in HCN channels, which has been shown previously to be important for the stable rhythmic firing of pacemaking neurons and could significantly affect synaptic integration.

Key words: spHCN; S4; VCF; Ih; voltage hysteresis; mode shift

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Received Aug. 31, 2006; revised Nov. 27, 2006; accepted Nov. 28, 2006.

Correspondence should be addressed to H. Peter Larsson, Neurological Sciences Institute, Oregon Health & Science University, 505 N.W. 185th Avenue, Beaverton, OR 97006. Email: larssonp{at}ohsu.edu

This article has been cited by other articles:

				A. K. Lyashchenko and G. R. Tibbs Ion binding in the Open HCN Pacemaker Channel Pore: Fast Mechanisms to Shape "Slow" Channels J. Gen. Physiol., February 25, 2008; 131(3): 227 - 243. [Abstract] [Full Text] [PDF]

				A. Bruening-Wright, F. Elinder, and H. P. Larsson Kinetic Relationship between the Voltage Sensor and the Activation Gate in spHCN Channels J. Gen. Physiol., July 1, 2007; 130(1): 71 - 81. [Abstract] [Full Text] [PDF]

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