Afterhyperpolarization
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Afterhyperpolarization, or AHP, is the hyperpolarizing phase of a neuron's action potential where the cell's membrane potential falls below the normal resting potential. This is also commonly referred to as an action potential's undershoot phase. AHPs have been segregated into "fast", "medium", and "slow" components that appear to have distinct ionic mechanisms and durations. While fast and medium AHPs can be generated by single action potentials, slow AHPs generally develop only during trains of multiple action potentials.[1]
Fast Afterhyperpolarization
[edit]Big conductance potassium channels (BK channels) are voltage- and calcium-gated potassium channels that sit very close to N-type calcium channels.[1][2] During a single action potential, BK channels open in response to membrane depolarization and the rapid influx of calcium. They do not close immediately when the cell repolarizes, which helps produce a quick repolarization phase and a fast after-hyperpolarization (fAHP) lasting about 2–5 ms. The fAHP is especially important in fast-firing neurons because this rapid repolarization supports repetitive firing and improves the precision of spike timing.[3]
Medium Afterhyperpolarization
[edit]Small conductance potassium channels (SK channels) are voltage-insensitive but activated by calcium. Together with the calcium-insensitive, voltage-gated Kv7 channels (also called KCNQ channels), they generate the medium after-hyperpolarization (mAHP), which typically lasts 10–100 ms.[4] SK channels are less tightly linked to calcium channels and usually respond only when multiple calcium channels open, which likely contributes to the slower onset of mAHPs.[2][5] The amplitude and timing of the mAHP help set the interval between spikes, creating a refractory period and regulating firing frequency.[6] SK channels also suppress long-term potentiation (LTP) by reducing dendritic EPSP amplitude, limiting NMDA receptor activation, and decreasing spike backpropagation.[7]
Slow Afterhyperpolarization
[edit]The channels responsible for the slow after-hyperpolarization (sAHP) are less well understood, but Kv7, KATP, and several other potassium channels have been implicated.[1][5][8] The sAHP current activates when somatic calcium rises during bursts of action potentials. Calcium-binding proteins such as hippocalcin and neurocalcin δ detect these larger, slower calcium increases and trigger a second-messenger cascade that releases PIP2, which then activates a mix of potassium channels. This indirect signaling pathway helps explain both the delayed onset and long duration of sAHPs, which can last from about 100 ms to several seconds.[5][8] sAHPs play several key roles: they make neurons less excitable after strong activity, prevent runaway or repetitive firing, stop afterdischarges, and help regulate rhythmic firing in certain neuron types.[1][9]
| AHP Type | Duration | Main Channels | Trigger | Physiological Role |
|---|---|---|---|---|
| Fast | 1–5 ms | BK | Ca²⁺, voltage | Spike repolarization, precision timing |
| Medium | 10–100 ms | SK, Kv7 | Ca²⁺, sometime voltage | Controls firing rate; sets interspike interval |
| Slow | 100 ms–1 s+ | Mixed K+ channels | Somatic Ca²⁺ | Prevents over-excitation; long-term inhibition |
Afterdepolarization
[edit]The afterhyperpolarized (sAHP) state can be followed by an afterdepolarized state (which is not to be confused with the cardiac afterdepolarization) and can thus set the phase of the subthreshold oscillation of the membrane potential, as reported for the stellate cells of the entorhinal cortex.[10] This mechanism is proposed to be functionally important to maintain the spiking of these neurons at a defined phase of the theta cycle, that, in turn, is thought to contribute to encoding of new memories by the medial temporal lobe of the brain [11]
References
[edit]- ^ a b c d Kshatri AS, Gonzalez-Hernandez A, Giraldez T (2018). "Physiological Roles and Therapeutic Potential of Ca2+ Activated Potassium Channels in the Nervous System". Front Mol Neurosci. 11 258. doi:10.3389/fnmol.2018.00258. PMC 6077210. PMID 30104956.
- ^ a b Bentzen BH, Olesen SP, Rønn LC, Grunnet M (2014). "BK channel activators and their therapeutic perspectives". Front Physiol. 5: 389. doi:10.3389/fphys.2014.00389. PMC 4191079. PMID 25346695.
- ^ Ancatén-González C, Segura I, Alvarado-Sánchez R, Chávez AE, Latorre R (February 2023). "Ca2+- and Voltage-Activated K+ (BK) Channels in the Nervous System: One Gene, a Myriad of Physiological Functions". Int J Mol Sci. 24 (4): 3407. doi:10.3390/ijms24043407. PMC 9967218. PMID 36834817.
- ^ Storm JF (February 1989). "An after-hyperpolarization of medium duration in rat hippocampal pyramidal cells". J Physiol. 409: 171–90. doi:10.1113/jphysiol.1989.sp017491. PMC 1190438. PMID 2585290.
- ^ a b c Andrade R, Foehring RC, Tzingounis AV (2012). "The calcium-activated slow AHP: cutting through the Gordian knot". Front Cell Neurosci. 6: 47. doi:10.3389/fncel.2012.00047. PMC 3480710. PMID 23112761.
- ^ Gu N, Vervaeke K, Hu H, Storm JF (August 2005). "Kv7/KCNQ/M and HCN/h, but not KCa2/SK channels, contribute to the somatic medium after-hyperpolarization and excitability control in CA1 hippocampal pyramidal cells". J Physiol. 566 (Pt 3): 689–715. doi:10.1113/jphysiol.2005.086835. PMC 1464792. PMID 15890705.
- ^ Baculis BC, Zhang J, Chung HJ (2020). "The Role of Kv7 Channels in Neural Plasticity and Behavior". Front Physiol. 11 568667. doi:10.3389/fphys.2020.568667. PMC 7530275. PMID 33071824.
- ^ a b Larsson HP (January 2013). "What determines the kinetics of the slow afterhyperpolarization (sAHP) in neurons?". Biophys J. 104 (2): 281–3. doi:10.1016/j.bpj.2012.11.3832. PMC 3552283. PMID 23442848.
- ^ Singh S, Shevtsova NA, Yao L, Rybak IA, Dougherty KJ (May 2025). "Properties of rhythmogenic currents in spinal Shox2 interneurons across postnatal development". J Physiol. 603 (10): 3201–21. doi:10.1113/JP287752. PMID 40349326.
- ^ Klink R, Alonso A (July 1993). "Ionic mechanisms for the subthreshold oscillations and differential electroresponsiveness of medial entorhinal cortex layer II neurons". J. Neurophysiol. 70 (1): 144–157. doi:10.1152/jn.1993.70.1.144. PMID 7689647.
- ^ Kovács KA (September 2020). "Episodic Memories: How do the Hippocampus and the Entorhinal Ring Attractors Cooperate to Create Them?". Frontiers in Systems Neuroscience. 14 559168: 68. doi:10.3389/fnsys.2020.559186. PMC 7511719. PMID 33013334.