Multiple types of Na+ currents mediate action potential electrogenesis in small neurons of mouse dorsal root ganglia

Abstract

Small (<25 microm in diameter) neurons of the dorsal root ganglion (DRG) express multiple voltage-gated Na(+) channel subtypes, two of which being resistant to tetrodotoxin (TTX). Each subtype mediates Na(+) current with distinct kinetic property. However, it is not known how each type of Na(+) channel contributes to the generation of action potentials in small DRG neurons. Therefore, we investigated the correlation between Na(+) currents in voltage-clamp recordings and corresponding action potentials in current-clamp recordings, using wild-type (WT) and Na(V)1.8 knock-out (KO) mice, to clarify the action potential electrogenesis in small DRG neurons. We classified Na(+) currents in small DRG neurons into three categories on the basis of TTX sensitivity and kinetic properties, i.e., TTX-sensitive (TTX-S)/fast Na(+) current, TTX-resistant (TTX-R)/slow Na(+) current, and TTX-R/persistent Na(+) current. Our concurrent voltage- and current-clamp recordings from the same neuron revealed that the action potentials in WT small DRG neurons were mainly dependent on TTX-R/slow Na(+) current mediated by Na(V)1.8. It was surprising that a large portion of TTX-S/fast Na(+) current was switched off in WT small DRG neurons due to a hyperpolarizing shift of the steady-state inactivation (h (infinity)), whereas in KO small DRG neurons which are devoid of TTX-R/slow Na(+) current, the action potentials were generated by TTX-S/fast Na(+) current possibly through a compensatory shift of h (infinity) in the positive direction. We also confirmed that TTX-R/persistent Na(+) current mediated by Na(V)1.9 actually regulates subthreshold excitability in small DRG neurons. In addition, we demon strated that TTX-R/persistent Na(+) current can carry an action potential when the amplitude of this current was abnormally increased. Thus, our results indicate that the action potentials in small DRG neurons are generated and regulated with a combination of multiple mechanisms that may give rise to unique functional properties of small DRG neurons.

Transient receptor potential cation channel, subfamily C, member 5 (TRPC5) is a cold-transducer in the peripheral nervous system

“…Increased functional availability of TRPM8 then may account for the avoidance of cold temperatures by TRPC5 −/− mice. Reminiscent of our findings in TRPC5 −/− mice, the compensatory replacement of functionally related tetrodotoxin-sensitive ion channels in Nav1.8-deficient mice (40) partially restored the loss of Nav1.8 function in the null-mutant nerve endings but not in their cultured DRG neurons (30,41). In both cases, the result is protection from cold via functionally overlapping but molecularly independent cold-detection mechanisms.…”

Altered Distribution of Juxtaparanodal Kv1.2 Subunits Mediates Peripheral Nerve Hyperexcitability in Type 2 Diabetes Mellitus

“…Previous studies suggested that PNH in diabetic patients could be a consequence of increased persistent nodal Na v -currents (Misawa et al, 2009). As these currents are mainly mediated by Na V 1.9 TTX-resistant (TTX-R) Na vchannels (Matsutomi et al, 2006), we tested the sensitivity of CAPs to TTX. The residual CAP amplitude was similar in WT and db/db nerves after exposure to 100 nM TTX (respectively 38 Ϯ 2% and 37 Ϯ 6%) and 1 M TTX (Ͻ2% for both tested genotypes).…”

Prostaglandin E2 Has No Effect on Two Components of Tetrodotoxin-Resistant Na+ Current in Mouse Dorsal Root Ganglion

“…We defined DRG neurons that were smaller than 25 µm in diameter as small neurons (26), and small neurons thus defined were used throughout the study. We employed KO DRG neurons (6,12,13) in addition to WT DRG neurons in this study. Unless otherwise specified, the experiments were performed in neurons from WT DRG.…”

“…Consequently, a possible involvement of I NaN has not been taken into consideration. In this study, therefore, we investigated the effect of PGE 2 on isolated I SNS or I NaN using wild-type (WT) as well as the Na V 1.8 knock-out (KO) mice (6,12,13). Unexpectedly, PGE 2 had no detectable effect on I SNS or I NaN , raising a question regarding the modulatory role of PGE 2 on TTX-R Na + current in inflammatory hyperalgesia.…”

“…The former component (which we refer to as I SNS ) activates and inactivates more slowly than TTX-sensitive Na + currents (4,5,13) and is thought to play a key role in action potential electrogenesis in small DRG neurons (7,13). The latter component (referred to as I NaN ) is characterized by extremely prolonged time courses of activation and inactivation at low activation voltages (9,12,14) and may regulate subthreshold excitability of small DRG neurons (9, 11 -13).…”