NaN, a novel voltage-gated Na channel, is expressed preferentially in peripheral sensory neurons and down-regulated after axotomy

Abstract

Although physiological and pharmacological evidence suggests the presence of multiple tetrodotoxinresistant (TTX-R) Na channels in neurons of peripheral nervous system ganglia, only one, SNS͞PN3, has been identified in these cells to date. We have identified and sequenced a novel Na channel ␣-subunit (NaN), predicted to be TTX-R and voltage-gated, that is expressed preferentially in sensory neurons within dorsal root ganglia (DRG) and trigeminal ganglia. The predicted amino acid sequence of NaN can be aligned with the predicted structure of known Na channel ␣-subunits; all relevant landmark sequences, including positively charged S4 and pore-lining SS1-SS2 segments, and the inactivation tripeptide IFM, are present at predicted positions. However, NaN exhibits only 42-53% similarity to other mammalian Na channels, including SNS͞PN3, indicating that it is a novel channel, and suggesting that it may represent a third subfamily of Na channels. NaN transcript levels are reduced significantly 7 days post axotomy in DRG neurons, consistent with previous findings of a reduction in TTX-R Na currents. The preferential expression of NaN in DRG and trigeminal ganglia and the reduction of NaN mRNA levels in DRG after axonal injury suggest that NaN, together with SNS͞PN3, may produce TTX-R currents in peripheral sensory neurons and may inf luence the generation of electrical activity in these cells.Voltage-gated Na channels in rat brain are composed of three subunits: the pore-forming ␣-subunit (260 kDa), which is sufficient to generate Na current flow across the membrane, and two auxiliary subunits, ␤1 (36 kDa) and ␤2 (33 kDa), which can modulate the properties of the ␣-subunit (1, 2). Nine distinct ␣-subunits have been identified in the rat (ref. 3 and references therein, refs. 4-6), and homologues have been cloned from various mammalian species, including humans (3). Specific ␣-subunits are expressed in a tissue-and developmentally specific manner (7). Aberrant expression patterns or mutations of voltage-gated sodium channel ␣-subunits underlie a number of human and animal disorders (1, 8-11).Multiple voltage-gated Na currents, some tetrodotoxinsensitive (TTX-S) and others TTX-resistant (TTX-R) (12-15), have been observed in dorsal root ganglia (DRG) neurons, which express multiple Na channel ␣-subunit mRNAs (16). The complex Na current profile in DRG neurons influences their excitability (13,(17)(18)(19) and may contribute to ectopic or spontaneous firing in these cells after injury to their axons (8,20,21).Excitability and Na current density are altered in neurons after axonal injury (22)(23)(24)(25). After axotomy, rat DRG neurons display dramatic changes in their TTX-R and TTX-S Na currents and in their Na channel mRNA profile; these changes include an attenuation of TTX-R and enhancement of TTX-S Na currents (21, 26), down-regulation of SNS͞PN3 transcripts and up-regulation of ␣III transcripts (20), and moderate elevation in the levels of ␣I and ␣II mRNAs (27). Inflammatory modulators also up-regulate TTX-R c...

ATP-sensitive potassium currents reduce the PGE2-mediated enhancement of excitability in adult rat sensory neurons

“…7) could result from the effect of cyclic GMP on TTX-R I Na rather than K ATP . However, TTX-R sodium channels are expressed in ∼80% of the small diameter sensory neurons (Novakovic et al 1998;Dib-Hajj et al 1998). If the actions of cyclic GMP were on TTX-R I Na only, then we would have expected to encounter ∼80% of the neurons to be sensitive to the inhibitory effects of cyclic GMP whereas we found that the sensitization produced by PGE 2 was reversed by 8-Br cyclic GMP in ∼50% of the small to medium diameter neurons (11 of 21).…”

Reduced thermal sensitivity and Nav1.8 and TRPV1 channel expression in sensory neurons of aged mice

“…Tetrodotoxin-resistant voltage-dependent sodium channels Nav1.8 (SNS) and Nav1.9 (NaN or SNS2) are selectively expressed in small/medium-sized nociceptive neurons and contribute to the production of an action potential in these neurons. In addition, functional studies reveal that Nav1.8 and Nav1.9 have a specialized role in mediating pain [1,2,[15][16][17]. Thus, the level of gene expression and/or distribution of these channels may be altered in aging neurons that have lowered sensitivity.…”

The Voltage-Gated Sodium Channel Nav1.9 Is an Effector of Peripheral Inflammatory Pain Hypersensitivity

“…The second step is initiation of action potentials in the nociceptors by voltage-gated sodium channels (VGSCs). Among the 10 VGSC isoforms, two, Na v 1.8 (Akopian et al, 1996;Sangameswaran et al, 1997) and Na v 1.9 (Dib-Hajj et al, 1998;Tate et al, 1998), are expressed almost exclusively by small nociceptor primary afferent neurons (Amaya et al, 2000) and are tetrodotoxin insensitive. Na v 1.8 generates a tetrodotoxin-resistant (TTXr) current with a threshold of activation of Ϫ40 mV that inactivates slowly (TTXrSlow) (Akopian et al, 1996;Sangameswaran et al, 1997;Renganathan et al, 2002b;John et al, 2004), whereas Na v 1.9 is presumed from recordings in Na v 1.8 null mice, to produce a persistent current with a more hyperpolarized voltage dependence and ultraslow recovery from inactivation (TTXr-Per) Baker et al, 2003).…”