ROMK inward-rectifier K ⁺ channels control renal K ⁺ secretion. The activity of ROMK is regulated by protein kinase A (PKA), but the molecular mechanism for regulation is unknown. Having found that direct interaction with membrane phosphatidylinositol 4,5-bisphosphate (PIP ₂ ) is essential for channel activation, we investigate here the role of PIP ₂ in regulation of ROMK1 by PKA. By using adenosine-5′-[γ-thio]triphosphate) (ATP[γS]) as the substrate, we found that PKA does not directly activate ROMK1 channels in membranes that are devoid of PIP ₂ . Rather, phosphorylation by PKA + ATP[γS] lowers the concentration of PIP ₂ necessary for activation of the channels. In solution-binding assays, anti-PIP ₂ antibodies bind PIP ₂ and prevent PIP ₂ –channel interaction. In inside-out membrane patches, antibodies inhibit the activity of the channels. PKA treatment then decreases the sensitivity of ROMK1 for inhibition by the antibodies, indicating an enhanced interaction between PIP ₂ and the phosphorylated channels. Conversely, mutation of the PKA phosphorylation sites in ROMK1 decreases PIP ₂ interaction with the channels. Thus, PKA activates ROMK1 channels by enhancing PIP ₂ –channel interaction.

Background: The reported prevalence and incidence rates of PD were significantly lower in China than those in Western countries. People in China and Taiwan have a similar ethnic background. Objective: To investigate the prevalence, incidence, and mortality rate of PD in Taiwan. Method: The authors conducted a population-based survey using a two-stage door-to-door approach for patients aged 40 years or older in Ilan, Taiwan. Patients were diagnosed with PD by having at least two of the four cardinal signs of parkinsonism and exclusion of seconddary parkinsonism. To identify new cases of PD after the survey, patients with negative results of parkinsonism in the first stage were matched to the information on clinical diagnosis of PD from the Bureau of National Health Insurance toward the end of December 31, 1997. All cases of PD were linked to the Taiwan mortality registration to ascertain causes of deaths until December 31, 1999. Results: The participation rate was 88.1% among the 11,411 contacted individuals. Thirty-seven cases of PD were identified. The age-adjusted prevalence rate of PD for all age groups was 130.1 per 100,000 population after being adjusted to the 1970 US census, assuming no cases of PD would be found among those younger than 40 years of age. Of 9972 non-PD subjects in the first screen, 15 new cases of PD were ascertained. The age-adjusted incidence rate was 10.4 per 100,000 population for all age groups. The case fatality rate of PD after a 7-year follow-up was 40.4% (21 deaths in 52 patients with PD). The relative risk of death for PD cases versus non-PD cases was 3.38 (95% CI: 2.05–4.34). The 5-year cumulative survival rate in PD cases (78.85%) was statistically lower than that in non-PD cases (92.84%). Conclusion: The prevalence and incidence rates of PD in Taiwan were much higher than those reported in China, but closer to those in Western countries. These results suggest that environmental factors may be more important than racial factors in the pathogenesis of PD.

The aim of this study was to investigate the association of the complex haplotype system of the adenosine triphosphate-binding cassette B1 (ABCB1) gene with the epilepsy treatment response. Ten polymorphisms were genotyped in 108 drug-resistant epileptic patients, 223 seizure-free patients and 287 normal controls. Highly significant linkage disequilibrium was shown among exon 12 C1236T, exon 21 G2677T and exon 26 C3435T. Haplotypic analysis demonstrated that patients with the CGC, TGC, and TTT haplotypes were more likely to be drug resistant. Further analysis of haplotype combinations demonstrated that drug-resistant patients tended to have the CGC/CGC, CGC/TGC, CGC/TTT, and TGC/TTT haplotype combinations over the seizure-free patients and controls (all p-values < 0.0001). In contrast, patients with the TTC/TTC, TTC/CGT, TTC/TGT, CGT/CGT and TGT/CGT haplotype combinations were more likely to be seizure-free (all p-values<0.0001 except CGT/CGT [p=0.0063]). Our results showed that the three loci, C1236T, G2677T and C3435T, jointly influenced the treatment response for epileptic patients. They should be regarded together as a complex polymorphic drug-response system. These findings suggest that examination of the haplotypes of the three loci could be useful in predicting drug resistance in epilepsy.

Background and purpose: Levetiracetam is an effective anti‐epileptic drug in the treatment of partial and generalized seizure. The purpose of the present study was to investigate whether levetiracetam regulates AMPA and NMDA receptor‐mediated excitatory synaptic transmission and to determine its site of action in the dentate gyrus (DG), the area of the hippocampus that regulates seizure activities.Experimental approach: Whole‐cell patch‐clamp method was used to record the AMPA and NMDA receptor‐mediated excitatory postsynaptic currents (EPSC_AMPAand EPSC_NMDA) in the presence of specific antagonists, from the granule cells in the DG in brain slice preparations from young Wistar rats (60–120 g).Key results: Levetiracetam (100 µM) inhibited both evoked EPSC_AMPAand EPSC_NMDAto an equal extent (80%), altered the paired‐pulse ratio (from 1.39 to 1.25), decreased the frequency of asynchronous EPSC and prolonged the inter‐event interval of miniature EPSC_AMPA(from 2.7 to 4.6 s) without changing the amplitude, suggesting a presynaptic action of levetiracetam. The inhibitory effect of levetiracetam on evoked EPSC_AMPAwas blocked by ω‐agatoxin TK (100 nM), a selective P/Q‐type voltage‐dependent calcium channel blocker, but not by nimodipine (10 µM) or ω‐conotoxin (400 nM).Conclusions and implications: These results suggest that levetiracetam modulated the presynaptic P/Q‐type voltage‐dependent calcium channel to reduce glutamate release and inhibited the amplitude of EPSC in DG. This effect is most likely to contribute to the anti‐epileptic action of levetiracetam in patients.