α2δ2 Controls the Function and Trans-Synaptic Coupling of Cav1.3 Channels in Mouse Inner Hair Cells and Is Essential for Normal Hearing.

The auxiliary subunit α2δ2 modulates the abundance and function of voltage-gated calcium channels. Here we show that α2δ2 mRNA is expressed in neonatal and mature hair cells. A functional α2δ2-null mouse, the ducky mouse (du), showed elevated auditory brainstem response click and frequency-dependent hearing thresholds. Otoacoustic emissions were not impaired pointing to normal outer hair cell function. Peak Ca2+ and Ba2+ currents of mature du/du inner hair cells (IHCs) were reduced by 30-40%, respectively, and gating properties, such as the voltage of half-maximum activation and voltage sensitivity, were altered, indicating that Cav1.3 channels normally coassemble with α2δ2 at IHC presynapses. The reduction of depolarization-evoked exocytosis in du/du IHCs reflected their reduced Ca2+ currents. Ca2+- and voltage-dependent K+ (BK) currents and the expression of the pore-forming BKα protein were normal. Cav1.3 and Cavß2 protein expression was unchanged in du/du IHCs, forming clusters at presynaptic ribbons. However, the close apposition of presynaptic Cav1.3 clusters with postsynaptic glutamate receptor GluA4 and PSD-95 clusters was significantly impaired in du/du mice. This implies that, in addition to controlling the expression and gating properties of Cav1.3 channels, the largely extracellularly localized α2δ2 subunit moreover plays a so far unknown role in mediating trans-synaptic alignment of presynaptic Ca2+ channels and postsynaptic AMPA receptors. SIGNIFICANCE STATEMENT: Inner hair cells possess calcium channels that are essential for transmitting sound information into synaptic transmitter release. Voltage-gated calcium channels can coassemble with auxiliary subunit α2δ isoforms 1-4. We found that hair cells of the mouse express the auxiliary subunit α2δ2, which is needed for normal hearing thresholds. Using a mouse model with a mutant, nonfunctional α2δ2 protein, we showed that the α2δ2 protein is necessary for normal calcium currents and exocytosis in inner hair cells. Unexpectedly, the α2δ2 protein is moreover required for the optimal spatial alignment of presynaptic calcium channels and postsynaptic glutamate receptor proteins across the synaptic cleft. This suggests that α2δ2 plays a novel role in organizing the synapse.

Incidence and relative survival of pancreatic adenocarcinoma and pancreatic neuroendocrine neoplasms in Germany, 2009-2018. An in-depth analysis of two population-based cancer registries.

BACKGROUND: Pancreatic neuroendocrine neoplasms are categorized as neuroendocrine tumors and neuroendocrine carcinomas. Until now, cancer registry reporting of pancreatic cancers does not include a stratification by these two subgroups. We studied the incidence and survival of pancreatic cancer with a special focus on pancreatic neuroendocrine neoplasms. METHODS: We analyzed data from the population-based cancer registries of North Rhine-Westphalia (NRW) and Saarland (SL), Germany, of the years 2009-2018. We included primary malignant pancreatic tumors and report morphology-specific age-standardized (World Standard population) incidence rates for ages 0-79 years and age-standardized relative survival (period approach, ICSS standard). All analyses were restricted to non-death certificate only cases. RESULTS: We analyzed 23,037 patients with a newly diagnosed primary pancreatic cancer. Among morphologically specified cancers, adenocarcinoma (92 %) and neuroendocrine neoplasms (7 %) were the most common morphologies. The age-standardized incidence rates of adenocarcinoma, neuroendocrine tumors and neuroendocrine carcinomas were 4.0-5.5 (in NRW and SL), 0.1-0.3, and 0.1-0.3 per 100,000 person-years, respectively. Neuroendocrine tumors had the highest age-standardized 5-year relative survival with 75.5 % (standard error, SE 2.3) in NRW and 90.6 % (SE 10.2) in SL followed by neuroendocrine carcinomas (NRW: 30.0 %, SE 3.1; SL: 32.3 %, SE 8.7) and adenocarcinomas (NRW: 11.3 %, SE 0.4; SL: 10.2 %, SE 1.5). DISCUSSION: The distinction between neuroendocrine tumors and neuroendocrine carcinomas by the WHO divides neuroendocrine neoplasms into two prognostically clearly distinct subgroups that should be separately analyzed in terms of survival. The first year after diagnosis of pancreatic cancer is the most critical year in terms of survival.