Blockage of HCN Channels Inhibits the Function of P2X Receptors in Rat Dorsal Root Ganglion Neurons

Lei, Xiaolu; Zeng, Junwei; Yan, Yan; Liu, Xiaohong

doi:10.1007/s11064-021-03509-5

Cited by 7 publications

(3 citation statements)

References 74 publications

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“…For example, Ma et al [24] found that intrathecal administration of HCN channel blockers ZD7288 attenuated the increase of cAMP levels in the spinal dorsal cord of diabetic neuropathic pain rats. Our previous study also showed that intrathecal injection of ZD7288 reduced the elevation of cAMP in DRG in rats with sciatic nerve injury [45]. How does HCN channel affect intracellular cAMP levels?…”

Section: Discussionmentioning

confidence: 89%

Activation of HCN channels caused by elevated cAMP levels in periaqueductal gray promotes bone cancer pain

Lei

Yan²,

Zeng³

et al. 2023

Neurochemistry International

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Section: Discussionmentioning

confidence: 89%

Activation of HCN channels caused by elevated cAMP levels in periaqueductal gray promotes bone cancer pain

Lei

Yan²,

Zeng³

et al. 2023

Neurochemistry International

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“…cannabinoids inhibit ATP-activated currents in rat trigeminal ganglionic neurons by activating CB1 receptors and inhibiting the adenylate cyclase-cAMP-PKA signaling pathway [53]. Recent studies have reported that blockage of HCN channels inhibits the function of P2X2 and P2X3 receptors in rat DRG neurons via a cAMP-PKA signaling pathway [54]. Leu-enkephalin inhibits P2X3 currents in DRG neurons through G i/o -proteins, while it increases P2X3 currents via a PLC signaling pathway after pre-treatment of the neurons with a G i/o -protein inhibitor PTX [55].…”

Section: Discussionmentioning

confidence: 99%

A1 Adenosine Receptor Activation Inhibits P2X3 Receptor–Mediated ATP Currents in Rat Dorsal Root Ganglion Neurons

Hao

Qiao

et al. 2022

Mol Neurobiol

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Purinergic signaling is involved in multiple pain processes. P2X3 receptor is a key target in pain therapeutics, while A1 adenosine receptor signaling plays a role in analgesia. However, it remains unclear whether there is a link between them in pain. The present results showed that the A1 adenosine receptor agonist N 6 -cyclopentyladenosine (CPA) concentration-dependently suppressed P2X3 receptor-mediated and α,β-methylene-ATP (α,β-meATP)-evoked inward currents in rat dorsal root ganglion (DRG) neurons.CPA signi cantly decreased the maximal current response of α,β-meATP, as shown a downward shift of its concentration-response curve. The CPA-induced suppression was independent on the clampingvoltageof the membrane. Inhibition of ATP currents by CPA was completely prevented by the A1 adenosine receptor antagonist KW-3902, and disappeared after the intracellular dialysis of either the G i/oprotein inhibitor pertussis toxin, the adenylate cyclase activator forskolin, or the cAMP analog 8-Br-cAMP.Morover, CPA suppressed the membrane potential depolarization and action potential burst induced by α,β-meATP in DRG neurons. Finally, CPA relieved α,β-meATP-induced nociceptive behaviors in rats by activating peripheral A1 adenosine receptors in dose-dependent manner. These results indicated that CPA inhibited P2X3 receptor activity in rat primary sensory neurons by activating A1 adenosine receptors, G i/oproteins and intracellular cAMP signaling, revealing a novel peripheral mechanism underlying its analgesic effect.

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“…This ionic current has unusually slow voltage-dependent activation kinetics and is a mixed, inwardly directed Na + /K + current that is sensitive to blocking by CsCl or ivabradine ( Cao et al, 2016 ; Hsiao et al, 2019 ). Activation of I h may cause the resting potential to depolarize and, in turn, reach the threshold required to generate or elicit an action potential; as a result, I h can affect pacemaker activity and impulse propagation ( Anastasaki et al, 2022 ; Lei et al, 2022 ; Peters et al, 2022 ). Moreover, the slow kinetics of I h in response to a long hyperpolarizing step can produce long-lasting, activity-dependent modification of membrane excitability in different excitable cell types ( Kretschmannova et al, 2012 ; Peters et al, 2021 ; Mäki-Marttunen and Mäki-Marttunen, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Concerted suppressive effects of carisbamate, an anti-epileptic alkyl-carbamate drug, on voltage-gated Na+ and hyperpolarization-activated cation currents

Hung

Huang

2023

Front. Cell. Neurosci.

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Carisbamate (CRS, RWJ-333369) is a new anti-seizure medication. It remains unclear whether and how CRS can perturb the magnitude and/or gating kinetics of membrane ionic currents, despite a few reports demonstrating its ability to suppress voltage-gated Na+ currents. In this study, we observed a set of whole-cell current recordings and found that CRS effectively suppressed the voltage-gated Na+ (INa) and hyperpolarization-activated cation currents (Ih) intrinsically in electrically excitable cells (GH3 cells). The effective IC50 values of CRS for the differential suppression of transient (INa(T)) and late INa (INa(L)) were 56.4 and 11.4 μM, respectively. However, CRS strongly decreased the strength (i.e., Δarea) of the nonlinear window component of INa (INa(W)), which was activated by a short ascending ramp voltage (Vramp); the subsequent addition of deltamethrin (DLT, 10 μM) counteracted the ability of CRS (100 μM, continuous exposure) to suppress INa(W). CRS strikingly decreased the decay time constant of INa(T) evoked during pulse train stimulation; however, the addition of telmisartan (10 μM) effectively attenuated the CRS (30 μM, continuous exposure)-mediated decrease in the decay time constant of the current. During continued exposure to deltamethrin (10 μM), known to be a pyrethroid insecticide, the addition of CRS resulted in differential suppression of the amplitudes of INa(T) and INa(L). The amplitude of Ih activated by a 2-s membrane hyperpolarization was diminished by CRS in a concentration-dependent manner, with an IC50 value of 38 μM. For Ih, CRS altered the steady-state I–V relationship and attenuated the strength of voltage-dependent hysteresis (Hys(V)) activated by an inverted isosceles-triangular Vramp. Moreover, the addition of oxaliplatin effectively reversed the CRS-mediated suppression of Hys(V). The predicted docking interaction between CRS and with a model of the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel or between CRS and the hNaV1.7 channel reflects the ability of CRS to bind to amino acid residues in HCN or hNaV1.7 channel via hydrogen bonds and hydrophobic interactions. These findings reveal the propensity of CRS to modify INa(T) and INa(L) differentially and to effectively suppress the magnitude of Ih. INa and Ih are thus potential targets of the actions of CRS in terms of modulating cellular excitability.

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Blockage of HCN Channels Inhibits the Function of P2X Receptors in Rat Dorsal Root Ganglion Neurons

Cited by 7 publications

References 74 publications

Activation of HCN channels caused by elevated cAMP levels in periaqueductal gray promotes bone cancer pain

Activation of HCN channels caused by elevated cAMP levels in periaqueductal gray promotes bone cancer pain

A1 Adenosine Receptor Activation Inhibits P2X3 Receptor–Mediated ATP Currents in Rat Dorsal Root Ganglion Neurons

Concerted suppressive effects of carisbamate, an anti-epileptic alkyl-carbamate drug, on voltage-gated Na+ and hyperpolarization-activated cation currents

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