Total plasma homocysteine, folate, and vitamin b12 status in healthy Iranian adults: the Tehran homocysteine survey (2003–2004)/a cross – sectional population based study

BACKGROUND: Elevated plasma total homocysteine is an independent risk factor for cardiovascular disease and a sensitive marker of the inadequate vitamin B12 and folate insufficiency. Folate and vitamin B12 have a protective effect on cardiovascular disease. This population based study was conducted to evaluate the plasma total homocysteine, folate, and vitamin B12 in healthy Iranian individuals. METHODS: This study was a part of the Cardiovascular Risk Factors Survey in the Population Lab Region of Tehran University has been designed and conducted based on the methodology of MONICA/WHO Project. A total of 1214 people aged 25–64 years, were recruited and assessed regarding demographic characteristics, homocysteine, folate, and vitamin B12 levels with interview, questionnaires, examination and blood sampling. Blood samples were gathered and analyzed according to standard methods. RESULTS: The variables were assessed in 1214 participants including 428 men (35.3%) and 786 women (64.7%). Age-adjusted prevalence of hyperhomocysteinemia (Hcy≥15 μmol/L) was 73.1% in men and 41.07% in women (P < 0.0001). Geometric mean of plasma homocysteine was 19.02 ± 1.46 μmol/l in men and 14.05 ± 1.45 μmol/l in women (P < 0.004) which increased by ageing. Age-adjusted prevalence of low serum folate level was 98.67% in men and 97.92% in women. Age-adjusted prevalence of low serum vitamin B12 level was 26.32% in men and 27.2% in women. Correlation coefficients (Pearson's r) between log tHcy and serum folate, and vitamin B12 indicated an inverse correlation (r = -0.27, r = -0.19, P < 0.0001, respectively). CONCLUSION: These results revealed that the prevalence of hyperhomocysteinemia, low folate and vitamin B12 levels are considerably higher than other communities. Implementation of preventive interventions such as food fortification with folic acid is necessary

Ca2+ Permeable AMPA Receptor Induced Long-Term Potentiation Requires PI3/MAP Kinases but Not Ca/CaM-Dependent Kinase II

Ca2+ influx via GluR2-lacking Ca2+-permeable AMPA glutamate receptors (CP-AMPARs) can trigger changes in synaptic efficacy in both interneurons and principle neurons, but the underlying mechanisms remain unknown. We took advantage of genetically altered mice with no or reduced GluR2, thus allowing the expression of synaptic CP-AMPARs, to investigate the molecular signaling process during CP-AMPAR-induced synaptic plasticity at CA1 synapses in the hippocampus. Utilizing electrophysiological techniques, we demonstrated that these receptors were capable of inducing numerous forms of long-term potentiation (referred to as CP-AMPAR dependent LTP) through a number of different induction protocols, including high-frequency stimulation (HFS) and theta-burst stimulation (TBS). This included a previously undemonstrated form of protein-synthesis dependent late-LTP (L-LTP) at CA1 synapses that is NMDA-receptor independent. This form of plasticity was completely blocked by the selective CP-AMPAR inhibitor IEM-1460, and found to be dependent on postsynaptic Ca2+ ions through calcium chelator (BAPTA) studies. Surprisingly, Ca/CaM-dependent kinase II (CaMKII), the key protein kinase that is indispensable for NMDA-receptor dependent LTP at CA1 synapses appeared to be not required for the induction of CP-AMPAR dependent LTP due to the lack of effect of two separate pharmacological inhibitors (KN-62 and staurosporine) on this form of potentiation. Both KN-62 and staurosporine strongly inhibited NMDA-receptor dependent LTP in control studies. In contrast, inhibitors for PI3-kinase (LY294002 and wortmannin) or the MAPK cascade (PD98059 and U0126) significantly attenuated this CP-AMPAR-dependent LTP. Similarly, postsynaptic infusion of tetanus toxin (TeTx) light chain, an inhibitor of exocytosis, also had a significant inhibitory effect on this form of LTP. These results suggest that distinct synaptic signaling underlies GluR2-lacking CP-AMPAR-dependent LTP, and reinforces the recent notions that CP-AMPARs are important facilitators of synaptic plasticity in the brain

Clustering and synaptic targeting of PICK1 requires direct interaction between the PDZ domain and lipid membranes

Protein interacting with c kinase 1 (PICK1) regulates the trafficking of receptors and ion-channels such as AMPA receptors. Traditionally, the PICK1 PDZ domain is regarded as an adaptor capable of binding to receptors trafficked by PICK1, and the lipid-binding BAR domain functions to tether PICK1 directly to membranes. Here, we show that the PICK1 PDZ domain can directly interact with lipid membranes. The PDZ domain and lipid membrane interaction is mediated by both a polybasic amino-acid cluster and a conserved ‘Cys-Pro-Cys' motif located away from the peptide ligand-binding groove. Disruption of the PDZ and lipid membrane interaction totally abolished synaptic targeting of PICK1. Although mutation of the CPC motif did not affect the interaction between PICK1 and AMPA receptors, the mutant PICK1 was unable to cluster the GluR2 subunit of the receptor. In neurons, PICK1 containing the same mutation displayed dramatically compromised capacity in the trafficking of AMPA receptors. Taken together, our findings not only uncovered the novel lipid membrane-binding property of the PICK1 PDZ domain, but also provided direct evidence supporting the functional relevance of the PDZ–lipid interaction