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Vincristine, a widely used chemotherapeutic agent for treating different cancer, often induces severe peripheral neuropathic pain. A common symptom of vincristine-induced peripheral neuropathic pain is mechanical allodynia and hyperalgesia. However, mechanisms underlying vincristine-induced mechanical allodynia and hyperalgesia are not well understood. In the present study, we show with behavioral assessment in rats that vincristine induces mechanical allodynia and hyperalgesia in a PIEZO2 channel-dependent manner since gene knockdown or pharmacological inhibition of PIEZO2 channels alleviates vincristine-induced mechanical hypersensitivity. Electrophysiological results show that vincristine potentiates PIEZO2 rapidly adapting (RA) mechanically-activated (MA) currents in rat dorsal root ganglion (DRG) neurons. We have found that vincristine-induced potentiation of PIEZO2 MA currents is due to the enhancement of static plasma membrane tension (SPMT) of these cells following vincristine treatment. Reducing SPMT of DRG neurons by cytochalasin D (CD), a disruptor of the actin filament, abolishes vincristine-induced potentiation of PIEZO2 MA currents, and suppresses vincristine-induced mechanical hypersensitivity in rats. Collectively, enhancing SPMT and subsequently potentiating PIEZO2 MA currents in primary afferent neurons may be an underlying mechanism responsible for vincristine-induced mechanical allodynia and hyperalgesia in rats. Targeting to inhibit PIEZO2 channels may be an effective analgesic method to attenuate vincristine-induced mechanical hypersensitivity.
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Aim To study the characteristics of KCNQ2/3 potassium channel expressed in CHO cells and its modulation by M_1 receptor.Methods KCNQ2 and KCNQ3 potassium channels and M_1 receptor were co-expressed in CHO cells.Whole cell patch-clamp techniques was used to observe the characteristics of KCNQ2/3 current,its modulation by the M_1 receptor,and the effects of the common potassium channel blockers.Results KCNQ2/3 current recorded in CHO cells was a slow-activation low-threshold non-inactivating,voltage-dependent outward potassium current.KCNQ2/3 current was elicited at about-60 mV,V_(1/2)(-26.8?1.2) mV and the deactivation current fitted two exponential function,with ?_(fast) of 101ms and ?_(slow) of 309 ms.The channel was not sensitive to common pharmacological blockers such as 4-AP,Ba~(2+) and TEA,but was inhibited significantly by linopirdine,with a IC_(50) of(6.5?0.83) ?mol?L~(-1).Acetylcholine suppressed the KCNQ2/3 current reversibly via M_1 receptor,with a IC_(50) of(0.7?0.05) ?mol?L~(-1).Conclusion KCNQ2 and KCNQ3 channels are the molecular basis of M-current observed in neuronal cells.KCNQ2/Q3 current expressed in CHO cells has similar characteristics as that seen in neuronal M-current.Linopirdine is a powerful blocker of KCNQ2/3 channel and acetylcholine inhibits the current by muscarinic M_1 receptor.This experiment has laid a solid basis for further study of M-current and KCNQ2/3 current,and is important for the study of neurological diseases relating to alteration of M-current,such as convulsion,epilepsy and Alzheimers disease.
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As an outward,voltage-dependent potassium channel,M type channel is crucial in the regulation of neuronal excitability;it is modulated by a variety of factors in vivo and its dysfunction often results in neuronal system diseases.Great efforts have been made to elucidate the mechanism underlying M channel modulation since its discovery decades ago.It is generally accepted that the Phospholipase C(PLC) signaling pathway plays a significant role in the M channel modulation.This review highlights the relationship between PLC signaling pathway and M channel modulation,as well as some recent progresses in the research of this field.
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Receptor tyrosine kinase(RTK),a membrane receptor superfamily with intrinsic protein tyrosine kinase activity,has many members and complicated signal transduction pathways.Activation of RTKs can trigger a series of signal transduction pathways and play essential roles in modulating cell growth,proliferation,differentiation and metabolism through influencing gene transcription and expression.Activation of RTK can also rapidly modulate some cellular functions including the modulation of ion channels.Potassium channels play a critical role in stabilization of membrane potential and regulation of cellular excitability.This review highlights the rapid modulation of potassium channels by RTKs and reviews the recent progress in related research.