Episodic ataxia (EA) is a rare, familial disorder producing attacks of generalized ataxia, with normal or near-normal neurological function between attacks. One type of EA is characterized by brief episodes of ataxia with myokymia (rippling of muscles) evident between attacks. Linkage studies in four such families suggested localization of an EA/myokymia gene near the voltage gated K+ channel gene, KCNA1 (Kv1.1), on chromosome 12p. Mutation analysis of the KCNA1 coding region in these families identified four different missense point mutations present in the heterozygous state, indicating that EA/myokymia can result from mutations in this gene.

The homeodomain transcription factors Arix/Phox2a and NBPhox/Phox2b play a role in the specification of the noradrenergic phenotype of central and peripheral neurons. To better understand the functions of these two factors, we have compared the genetic organization, chromosomal location, and transcriptional regulatory properties of Arix and NBPhox. The gene structure is very similar, with each gene containing three exons and two introns, extending a total of approximately 5 kb. Arix and NBPhox are unlinked in human and mouse genomes. NBPhox is located on human Chromosome 4p12 and mouse Chromosome 5, while Arix is located on human Chromosome 11q13 and mouse Chromosome 7. Both proteins bind to three sites in the promoter proximal region of the rat dopamine beta-hydroxylase gene (DBH). In vitro, Arix and NBPhox form DNA-independent multimers and exhibit cooperative binding to the DB1 regulatory element, which contains two homeodomain recognition sites. Both proteins regulate transcription from the rat DBH promoter, and transcription is synergistically increased in the presence of the protein kinase A catalytic subunit (PKA) plus either Arix or NBPhox. The transcription factors exhibit similar concentration-dependent efficacies, and when they are coexpressed, transcription is stimulated to a value approximately equal to that seen with either factor alone. The N-terminal segment of Arix is essential for transcriptional regulatory activity, and this region bears 50% identity with NBPhox, suggesting a similar mechanism of transcriptional activation of the DBH gene. We conclude from this study that Arix and NBPhox exhibit indistinguishable and independent transcriptional regulatory properties on the DBH promoter.

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A sixth family with autosomal dominantly inherited myokymia and paroxysmal ataxia is described. The syndrome in this family is linked to the recently discovered locus for inherited myokymia and paroxysmal ataxia on the human chromosome 12p, and a missense mutation is shown in the KCNA1 gene.

In the present investigation, we test the hypothesis that progesterone can rapidly relax, via a nongenomic mechanism, persistent flow occluding, agonist-activated coronary artery (CA) vasospasm, and hyperreactive vascular muscle cell (VMC) Ca(2+) responses in ovariectomized rhesus monkeys. CA vasospasm, induced by injection of 100 microM serotonin and 1 microM U-46619 (5-HT+U; 1 ml/30 s), resulted in a decrease in CA diameter (phi) from 1.8 +/- 0.2 to 0.3 +/- 0.1 mm at the site of focal constriction. Injection of 100 ng progesterone into the CA significantly relieved the severe vasoconstriction (1.3 +/- 0.2 mm) and reestablished distal flow in 3 min; the preconstriction phi was completely restored in 8.2 +/- 2.6 min (n = 6). Similarly, cell impermeant albumin-conjugated progesterone, but not albumin-conjugated 17 beta-estradiol, decreased 5-HT+U stimulated VMC Ca(2+) responses (250 +/- 34% of basal 30 min after stimulation) back to the prestimulation level (113 +/- 17% of basal) in 25 min (half time = 7 min). The presence of a rapid vasodilator action of progesterone in the primate CA and isolated VMC suggests its benefits in hormone replacement therapy may also include nongenomic vascular relaxant actions.