Social Security and Medicare : the impending fiscal challenge

Social Security—and the solvency of its Trust Fund—have increasingly become a focus of discussion in the media and policy circles. The basic problem is that promised benefits will soon exceed program revenues. Without changes in benefits or funding, the Trustees of Social Security project that assets in the Trust Fund will be depleted in 2041. While Social Security is a serious problem for taxpayers and beneficiaries, Medicare poses an even greater challenge. Together, the two programs’ benefits currently amount to about 6 percent of GDP. By 2080 they are projected to swell to 20 percent. With spending on these two programs projected to grow faster than the nation’s GDP, the Board of Trustees of Social Security and Medicare have concluded that “We do not believe the currently projected long-run growth rates of Social Security and Medicare are sustainable under current financing arrangements.” To keep the programs solvent without slashing benefits or increasing tax revenues, the federal budget deficit would need to grow drastically. Thus changes will likely be needed to the structure of the two programs. In fact, any viable solution is likely to involve changes in government spending and taxes. Hakkio and Wiseman provide a framework for understanding the nature of the fiscal challenges posed by Social Security and Medicare—a prerequisite for finding specific solutionsSocial security ; Medicare

Nicotine up-regulates α4β2 nicotinic receptors and ER exit sites via stoichiometry-dependent chaperoning

The up-regulation of α4β2* nicotinic acetylcholine receptors (nAChRs) by chronic nicotine is a cell-delimited process and may be necessary and sufficient for the initial events of nicotine dependence. Clinical literature documents an inverse relationship between a person’s history of tobacco use and his or her susceptibility to Parkinson’s disease; this may also result from up-regulation. This study visualizes and quantifies the subcellular mechanisms involved in nicotine-induced nAChR up-regulation by using transfected fluorescent protein (FP)-tagged α4 nAChR subunits and an FP-tagged Sec24D endoplasmic reticulum (ER) exit site marker. Total internal reflection fluorescence microscopy shows that nicotine (0.1 µM for 48 h) up-regulates α4β2 nAChRs at the plasma membrane (PM), despite increasing the fraction of α4β2 nAChRs that remain in near-PM ER. Pixel-resolved normalized Förster resonance energy transfer microscopy between α4-FP subunits shows that nicotine stabilizes the (α4)2(β2)3 stoichiometry before the nAChRs reach the trans-Golgi apparatus. Nicotine also induces the formation of additional ER exit sites (ERES). To aid in the mechanistic analysis of these phenomena, we generated a β2enhanced-ER-export mutant subunit that mimics two regions of the β4 subunit sequence: the presence of an ER export motif and the absence of an ER retention/retrieval motif. The α4β2enhanced-ER-export nAChR resembles nicotine-exposed nAChRs with regard to stoichiometry, intracellular mobility, ERES enhancement, and PM localization. Nicotine produces only small additional PM up-regulation of α4β2enhanced-ER-export receptors. The experimental data are simulated with a model incorporating two mechanisms: (1) nicotine acts as a stabilizing pharmacological chaperone for nascent α4β2 nAChRs in the ER, eventually increasing PM receptors despite a bottleneck(s) in ER export; and (2) removal of the bottleneck (e.g., by expression of the β2enhanced-ER-export subunit) is sufficient to increase PM nAChR numbers, even without nicotine. The data also suggest that pharmacological chaperoning of nAChRs by nicotine can alter the physiology of ER processes