Gating (electrophysiology)

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In electrophysiology, the term gating refers to the opening (activation) or closing (by deactivation or inactivation) of ion channels.[1]

When ion channels are in a 'closed' (non-conducting) state, they are impermeable to ions and do not conduct electrical current. When ion channels are in an open state, they conduct electrical current by allowing some ions to pass through them, and thus across the plasma membrane of the cell. These flows of ions across the membrane result in an electrical current across the membrane. Gating is the process of an ion channel transforming between any of its conducting and non-conducting states.

The name 'gating' derives from the idea that an ion channel protein includes a pore that is guarded by a gate or several gates, and the gate(s) must be in the open position for any ions to pass through the pore. A variety of cellular changes can trigger gating, depending on the ion channel, including changes in voltage across the cell membrane (voltage-gated ion channels), drugs or hormones interacting with the ion channel (ligand-gated ion channels), changes in temperature,[2] stretching or deformation of the cell membrane, addition of a phosphate group to the ion channel (phosphorylation), and interaction with other molecules in the cell (e.g., G proteins).[3] The rate at which any of these gating processes occurs in response to these triggers are known as the 'kinetics of gating.' Some drugs and many ion channel toxins act as 'gating modifiers' of voltage-gated ion channels by changing the kinetics of gating.

The voltage-gated ion channels of the action potential are often described as having four gating processes: activation, deactivation, inactivation, and reactivation (also called 'recovery from inactivation'). In a model of an ion channel that has two gates (an activation gate and an inactivation gate) that must both be open for ions to be conducted through the channel, 'activation' is the process of opening the activation gate, which occurs in response to the voltage inside the cell membrane (the membrane potential) becoming more positive with respect to the outside of the cell (depolarization); 'deactivation' is the opposite process of the activation gate closing in response to the inside of the membrane becoming more negative (repolarization). 'Inactivation' is the closing of the inactivation gate; as with activation, inactivation occurs in response to the voltage inside the membrane becoming more positive, but often inactivation is found to be delayed in time compared to activation. 'Recovery from inactivation' is the opposite of inactivation. Thus, both inactivation and deactivation are processes that lead to the channel becoming non-conducting, but they are different processes in that inactivation is triggered by the membrane potential becoming more positive, whereas deactivation is triggered by the membrane potential becoming more negative.

Activation[edit]

Voltage-gated ion channels[edit]

Voltage-gated ion channel. When the membrane is polarized, the voltage sensing domain of the channel shifts, opening the channel to ion flow (ions represented by yellow circles).

Voltage-gated ion channels react to the voltage differential across the membrane. Portions of the channel domain act as voltage sensors. As the membrane is depolarized, the change in electrostatic forces moves these voltage sensing domains, thus changing the conformation of the channel and opening the pore.[4]

Ligand-gated ion channels[edit]

Ligand-gated ion channels react to the binding of ligands. When a ligand is not present, the channel remains in its resting, closed conformation. When the ligand is present, the ligand will bind to an extracellular receptor on or near the channel, which results in a conformational change in the channel, opening the pore to ion permeation.[5]

Inactivation[edit]

Inactivation occurs while the channel remains open, but stops passing ions. A second gate may close on the channel, blocking ion permeation, while the channel is still in its open state.

Ball and chain inactivation[edit]

Voltage-gated ion channel in its closed, open, and inactivated states. The inactivated channel is still in its open state, but the ball domain blocks ion permeation.

The ball and chain model, also known as N-type inactivation or hinged lid inactivation, is a gating mechanism for some voltage-gated ion channels. Voltage-gated ion channels are composed of four[dubious ] α subunits, one or more of which will have a ball domain located on its cytoplasmic N-terminus.[6] The ball domain is electrostatically attracted to the inner channel domain. When the ion channel is activated, the inner channel domain is exposed, and within milliseconds the chain will fold and the ball will enter the channel, occluding ion permeation.[7] The channel returns to its closed state, blocking the channel domain, and the ball leaves the pore.[8]

Deactivation[edit]

As the membrane potential returns to its resting value, the voltage differential is not sufficient to keep the channel in its open state, causing the channel to close.

Deactivation is the closing of the ion channel pore. For voltage-gated channels this occurs when the voltage differential that originally caused the channel to open returns to its resting value.[9] For ligand-gated channels this occurs when the ligand dissociates from the channel's receptor binding site.

See also[edit]

References[edit]

  1. ^ Alberts, Bruce; Bray, Dennis; Lewis, Julian; Raff, Martin; Roberts, Keith; Watson, James D. (1994). Molecular biology of the cell. New York: Garland. pp. 523–547. ISBN 978-0-8153-1620-6.
  2. ^ Cesare P, Moriondo A, Vellani V, McNaughton PA (July 1999). "Ion channels gated by heat". Proc. Natl. Acad. Sci. U.S.A. 96 (14): 7658–63. doi:10.1073/pnas.96.14.7658. PMC 33597. PMID 10393876.
  3. ^ Hille, Bertil (2001). Ion channels of excitable membranes. Sunderland, Mass: Sinauer. ISBN 978-0-87893-321-1.
  4. ^ Bähring, Robert; Covarrubias, Manuel (2011-01-28). "Mechanisms of closed-state inactivation in voltage-gated ion channels". The Journal of Physiology. 589 (3): 461–479. doi:10.1113/jphysiol.2010.191965. ISSN 0022-3751. PMC 3055536. PMID 21098008.
  5. ^ "Gene group | HUGO Gene Nomenclature Committee". www.genenames.org. Retrieved 2018-11-22.
  6. ^ "Modulation of K+ channel N-type inactivation by sulfhydration through hydrogen sulfide and polysulfides". rdcu.be. Retrieved 2018-11-22.
  7. ^ Holmgren, M.; Jurman, M. E.; Yellen, G. (September 1996). "N-type inactivation and the S4-S5 region of the Shaker K+ channel". The Journal of General Physiology. 108 (3): 195–206. doi:10.1085/jgp.108.3.195. ISSN 0022-1295. PMC 2229322. PMID 8882863.
  8. ^ Bénitah, J. P.; Chen, Z.; Balser, J. R.; Tomaselli, G. F.; Marbán, E. (1999-03-01). "Molecular dynamics of the sodium channel pore vary with gating: interactions between P-segment motions and inactivation". The Journal of Neuroscience. 19 (5): 1577–1585. doi:10.1523/JNEUROSCI.19-05-01577.1999. ISSN 0270-6474. PMID 10024345.
  9. ^ Bähring, Robert; Covarrubias, Manuel (2011-01-28). "Mechanisms of closed-state inactivation in voltage-gated ion channels". The Journal of Physiology. 589 (3): 461–479. doi:10.1113/jphysiol.2010.191965. ISSN 0022-3751. PMC 3055536. PMID 21098008.