KCNQ/M Currents in Sensory Neurons: Significance for Pain Therapy

Passmore, Gayle M.; Selyanko, A. A.; Mistry, Mohini; AlQatari, Mona; Marsh, Stephen J.; Matthews, Elizabeth; Dickenson, Anthony H.; Brown, Terry; Burbidge, Stephen A.; Main, Martin J.; Brown, David A.

doi:10.1523/jneurosci.23-18-07227.2003

Cited by 335 publications

(433 citation statements)

References 47 publications

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“…1. Two voltagedependent exponential time constants were required to fit the deactivation of the M-current, in agreement with previous measurements (12,17), and neither their amplitudes nor their voltage-dependences are affected by expression of either fusion protein (Fig. 2 D and E).…”

Section: Expression Of a Cam-binding Fusion Protein Decreases The Neusupporting

confidence: 87%

Expression of a calmodulin-binding KCNQ2 potassium channel fragment modulates neuronal M-current and membrane excitability

Shahidullah

Santarelli

Hua

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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KCNQ2 and KCNQ3 ion channel pore-forming subunits coassemble to form a heteromeric voltage-gated potassium channel that underlies the neuronal M-current. We and others showed that calmodulin (CaM) binds to specific sequence motifs in the C-terminal domain of KCNQ2 and KCNQ3. We also found that a fusion protein containing a KCNQ2 CaM-binding motif, coexpressed with KCNQ2 and KCNQ3, competes with the full-length KCNQ2 channel for CaM binding and thereby decreases KCNQ2͞3 current density in heterologous cells. We have explored the importance of CaM binding for the generation of the native M-current and regulation of membrane excitability in rat hippocampal neurons in primary cell culture. M-current properties were studied in cultured neurons by using whole-cell patch clamp recording. The M-current density is lower in neurons expressing the CaM-binding motif fusion protein, as compared to control neurons transfected with vector alone. In contrast, no change in M-current density is observed in cells transfected with a mutant fusion protein that is unable to bind CaM. The CaM-binding fusion protein does not influence the rapidly inactivating A-current or the large conductance calciumactivated potassium channel-mediated fast spike afterhyperpolarization in neurons in which the M-current is suppressed. Furthermore, the CaM-binding fusion protein, but not the nonbinding mutant, increases both the number of action potentials evoked by membrane depolarization and the size of the spike afterdepolarization. These results suggest that CaM binding regulates M-channel function and membrane excitability in the native neuronal environment.A-current ͉ afterdepolarization ͉ afterhyperpolarization T he neuronal M-current is a voltage-dependent potassium current with distinct biophysical characteristics: activation in the subthreshold range of membrane voltage, slow activation and deactivation kinetics, and no inactivation. This current originally was named the M-current because it could be suppressed by muscarine and other agonists that activate muscarinic acetylcholine receptors (1). Its unique combination of biophysical properties, most notably its slow gating, activation at negative voltages, and lack of inactivation, results in sustained activity of the M-current near the action potential threshold. Because it is the major sustained outward current in this voltage range, it plays a dominant role in regulating neuronal excitability (2).The M-current is ubiquitous in vertebrate central and peripheral neurons (reviewed in ref.3). It is modulated by the activation of multiple receptor types, including those for classical neurotransmitters such as acetylcholine, serotonin, noradrenaline, and glutamate. In addition, a number of peptide modulators, among which are opioid peptides, somatostatin, angiotensin-II, substance P, bradykinin, and luteinizing hormone releasing hormone can modulate the M-current (e.g., see refs. 3-5). The fact that the M-current is a target for the actions of so many neuromodulators and synaptic neurotransmitter...

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Section: Expression Of a Cam-binding Fusion Protein Decreases The Neusupporting

confidence: 87%

Expression of a calmodulin-binding KCNQ2 potassium channel fragment modulates neuronal M-current and membrane excitability

Shahidullah

Santarelli

Hua

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…First, it inhibits a potassium current carried by Kv7.2/Kv7.3 channels, the so-called M-current; this causes the cells to depolarize and to fire more action potentials when challenged with a depolarizing current - i.e., they are more excitable. This itself is not that unexpected (though not previously shown in sensory neurons), since the M-current had already been identified in nociceptive sensory neurons (6), and the authors (7) and others (8) have previously shown that M-current inhibition is the cause of the excitatory action of bradykinin on sympathetic neurons. However, the second effect is new: the authors report that the rise in Ca 2+ concentration also activates a calciumdependent chloride current.…”

Section: Patwardhan Et Al In This Issue Of the Jci Identifies Oxidizsupporting

confidence: 59%

Some new insights into the molecular mechanisms of pain perception

Brown¹,

Passmore²

2010

J. Clin. Invest.

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Bradykinin is the most potent endogenous inducer of acute pain. However, the way in which it excites nociceptive sensory nerve endings is still unclear. In an article recently published in the JCI, Liu et al. suggest a new mechanism via which bradykinin induces acute spontaneous pain. The authors report that the stimulation of B 2 bradykinin receptors by bradykinin triggers the release of intracellular calcium ions from nociceptive sensory neurons of rat dorsal root ganglia. This depolarizes the sensory nerve endings by simultaneously closing M-type potassium channels and opening TMEM16A chloride channels, resulting in the production of nociceptive signals. Here, we discuss the relationship between this effect and a previously described mechanism for pain sensitization and evaluate its potential significance for therapeutic pain control. A separate study by Patwardhan et al. in this issue of the JCI identifies oxidized linoleic acid metabolites as novel mediators of thermally induced pain.Bradykinin is the most potent endogenous pain-producing substance known (1, 2). It is a 9-amino acid peptide that is clipped off from a 110-kDa precursor plasma a-globulin termed kininogen by the serine protease kallikrein (Figure 1). Kallikrein is formed from an inactive precursor, prekallikrein. In damaged tissue, this conversion of prekallikrein to kallikrein is accelerated by clotting factor XII (also known as Hageman factor); this occurs, along with the formation of bradykinin, when the three generator proteins (Hageman factor, prekallikrein, and kininogen) come into contact with negatively charged cell surfaces such as those of endothelial cells (3). Once formed, bradykinin is quite rapidly inactivated in the plasma and lungs by peptidases called kininases, so its effects are largely confined to the tissues where it is formedi.e., it acts as a local inflammatory mediator and induces nocifensive responses.In the short term at least, the pain-inducing effects of bradykinin are produced by activation of a G protein-coupled receptor termed the B 2 receptor, though an additional receptor called the B 1 receptor may be induced during long-term inflammation. Two components of nocifensive action have been identified (1, 2) -a direct activation of sensory nerve endings and a sensitization of sensory nerves to other noxious and non-noxious stimuli (termed hyperalgesia and allodynia, respectively). The mechanism of bradykinin-induced hypersensitivity is now quite well understood (4): it is due to increased temperature sensitivity of the transient receptor potential cation channel, subfamily V, member 1 (TRPV1) in sensory axons (see A messenger for the pain induced by noxious heat?). These channels normally respond only to noxious heat (above 42°C), but, after exposure to bradykinin, they respond to much lower, ambient temperatures. (This would explain why, after a sunburn, a normally pleasant shower temperature becomes painful.) However, in spite of much previous work, a universally acceptable mechanism for the direct nociceptive ac...

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“…The pharmacology of this particular channel type has already started to be investigated as the channel might also be of interest in neuropathic pain, 48 epilepsy 49,50 and to improve memory. 42 …”

Section: Pp2a-bc and Kcnq2 In Bipolar Diseasementioning

confidence: 99%

PP2A-Bγ subunit and KCNQ2 K+ channels in bipolar disorder

Borsotto

Cavarec²,

Bouillot³

et al. 2006

Pharmacogenomics J

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Many bipolar affective disorder (BD) susceptibility loci have been identified but the molecular mechanisms responsible for the disease remain to be elucidated. In the locus 4p16, several candidate genes were identified but none of them was definitively shown to be associated with BD. In this region, the PPP2R2C gene encodes the Bg-regulatory subunit of the protein phosphatase 2A (PP2A-Bg). First, we identified, in two different populations, single nucleotide polymorphisms and risk haplotypes for this gene that are associated to BD. Then, we used the Bg subunit as bait to screen a human brain cDNA library with the yeast two-hybrid technique. This led us to two new splice variants of KCNQ2 channels and to the KCNQ2 channel itself. This unusual K þ channel has particularly interesting functional properties and belongs to a channel family that is already known to be implicated in several other monogenic diseases. In one of the BD populations, we also found a genetic association between the KCNQ2 gene and BD. We show that KCNQ2 splice variants differ from native channels by their shortened C-terminal sequences and are unique as they are active and exert a dominant-negative effect on KCNQ2 wild-type (wt) channel activity. We also show that the PP2A-Bg subunit significantly increases the current generated by KCNQ2wt, a channel normally inhibited by phosphorylation. The kinase glycogen synthase kinase 3 beta (GSK3b) is considered as an interesting target of lithium, the classical drug used in BD. GSK3b phosphorylates the KCNQ2 channel and this phosphorylation is decreased by Li þ .

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KCNQ/M Currents in Sensory Neurons: Significance for Pain Therapy

Cited by 335 publications

References 47 publications

Expression of a calmodulin-binding KCNQ2 potassium channel fragment modulates neuronal M-current and membrane excitability

Expression of a calmodulin-binding KCNQ2 potassium channel fragment modulates neuronal M-current and membrane excitability

Some new insights into the molecular mechanisms of pain perception

PP2A-Bγ subunit and KCNQ2 K+ channels in bipolar disorder

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