Nav Nav1.5 and 1.9, whose role has not been

Nav channels are responsible for the rapid upstroke of the action potential in almost all excitable cellsfrom heart, skeletal muscle to brain1. The Nav channel signaling complex is made-up of a pore-forming?-subunit which assembles as four homologous domains (DI, DII, DIII, and DIV) of sixtransmembrane segments (S1–S6)2 (Fig. 3c). To date, nine ?-subunit genes have been identified(Nav1.1-???)1-3. The channel complex often contains auxiliary ?-subunits (??-?4) which can alterchannel function4,5.

In the CNS, it is generally assumed that neuronal excitability is governed bytetrodotoxin (TTX)-sensitive Nav channels, Nav1.1, 1.2 and 1.6. However, the CNS also expressesTTX-resistant Nav channels, Nav1.5 and 1.9, whose role has not been investigated in any detail.Nav1.

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5 and Nav1.9 are already known for their roles outside the CNS. Nav1.

5 is responsible forgenerating the cardiac action potential6 whereas Nav1.9 transmits information associated withinflammatory pain7. What has emerged from this work on cardiac tissue is that Nav1.5 exists asmultiple isoforms which would have to be considered in any analysis of the CNS. Although Nav1.

9mutations are found in rare cases of genetic pain disease7, it remains to be investigated if the Nav1.9gene is subject to alternate splicing whether in the CNS or elsewhere7.The Nav1.5 gene is expressed as one of nine possible splice variants, 4 of which are functional8,namely Nav1.5a, c, d and e8. Nav1.5a results from deletion of exon 18 that encodes 53 amino acids ofthe cytoplasmic linker of domains II-III (Fig.

3c). Transcripts of Nav1.5a are found in rat whole brain9as well as dorsal root ganglion neurons10,11 and cardiac tissue. Nav1.5c differs from the full-lengthchannel by a single amino acid which is added at the exon 17 /18 junction (Fig. 3c)8. Expressed atrelatively high levels in the human heart, Nav1.

5c is also detected in brain transcripts12. Nav1.5dcorresponds to an in-frame deletion of 40 residues of exon 17 (Fig. 3c) in heart tissue13 8 but has yet tobe studied in the CNS. Finally, Nav1.5e was first found in human cancer cell lines and corresponds tothe alternative splicing of exon 6 which encodes part of the S3-S4 voltage sensor of domain I (DI)(Figs. 3c and 5a)14,15.

Residues Y205-P234 of exon 6a are found in Nav1.5e compared to Y205-P234 ofexon 6b in mH1 (Fig. 3c). Nav1.5e is downregulated during heart development and absent from theadult and thus is referred to as neonatal Nav1.5 8,16.

Transcripts of Nav1.5e have been reported in adultCNS tissue17,18 though where exactly in the brain remains to be examined.To explore this, we will study the expression pattern and role of Nav1.5 and Nav1.

9 in the wildtype(WT) and FXS brain. Experiments in Projects I and II will determine the distribution and functionalproperties of Nav channel signaling complexes whereas Project III will examine their role in the WTand FXS brain. Due to space limitations, it was not possible to show all our preliminary data andtherefore we have indicated “data not shown” when it is discussed in the following sections.