GTP‐induced tetrodotoxin‐resistant Na+ current regulates excitability in mouse and rat small diameter sensory neurones

MD Baker, SY Chandra, Y Ding… - The Journal of …, 2003 - Wiley Online Library
MD Baker, SY Chandra, Y Ding, SG Waxman, JN Wood
The Journal of physiology, 2003Wiley Online Library
Peripheral pain thresholds are regulated by the actions of inflammatory mediators. Some act
through G‐protein‐coupled receptors on voltage‐gated sodium channels. We have found
that a low‐threshold, persistent tetrodotoxin‐resistant Na+ current, attributed to NaV1. 9, is
upregulated by GTP and its non‐hydrolysable analogue GTP‐γ‐S, but not by GDP. Inclusion
of GTP‐γ‐S (500 μm) in the internal solution led to an increase in maximal current amplitude
of> 300% within 5 min. In current clamp, upregulation of persistent current was associated …
Peripheral pain thresholds are regulated by the actions of inflammatory mediators. Some act through G‐protein‐coupled receptors on voltage‐gated sodium channels. We have found that a low‐threshold, persistent tetrodotoxin‐resistant Na+ current, attributed to NaV1.9, is upregulated by GTP and its non‐hydrolysable analogue GTP‐γ‐S, but not by GDP. Inclusion of GTP‐γ‐S (500 μm) in the internal solution led to an increase in maximal current amplitude of > 300 % within 5 min. In current clamp, upregulation of persistent current was associated with a more negative threshold for action potential induction (by 15–16 mV) assessed from a holding potential of −90 mV. This was not seen in neurones without the low‐threshold current or with internal GDP (P < 0.001). In addition, persistent current upregulation depolarized neurones. At −60 mV, internal GTP‐γ‐S led to the generation of spontaneous activity in initially silent neurones only when persistent current was upregulated. These findings suggest that regulation of the persistent current has important consequences for nociceptor excitability.
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