Significance: The L-type voltage-gated calcium channel Cav1.2 mediates depolarization-triggered signaling cascades that regulate neuronal-specific transcription factors such as CREB and immediate-early genes. We demonstrate that the interaction of the intracellular β-subunit of the channel with H-Ras is indispensable for depolarization-triggered gene activation. The binding of the recombinant β-subunit to H-Ras and H-Ras pulldown assays confirms the ability of H-Ras to physically interact with the β-subunit. We show that gene transcription also requires the binding of Ca ²⁺ to the channel pore and is calcium-influx independent. These results delineate Cav1.2–H-Ras interaction by extracellular signaling as a mode of rapid induction of gene transcription. They expand the repertoire of Cav1.2 metabotropic signaling triggered by depolarization-induced conformational changes, which require channel-pore occupancy and are calcium-influx independent.

Pollen grains transport the sperm cells through the style tissue via a fast-growing pollen tube to the ovaries where fertilization takes place. Pollen tube growth requires a precisely regulated network of cellular as well as molecular events including the activity of the plasma membrane H⁺ ATPase, which is known to be regulated by reversible protein phosphorylation and subsequent binding of 14-3-3 isoforms. Immunodetection of the phosphorylated penultimate threonine residue of the pollen plasma membrane H⁺ ATPase (LilHA1) of Lilium longiflorum pollen revealed a sudden increase in phosphorylation with the start of pollen tube growth. In addition to phosphorylation, pH modulated the binding of 14-3-3 isoforms to the regulatory domain of the H⁺ ATPase, whereas metabolic components had only small effects on 14-3-3 binding, as tested with in vitro assays using recombinant 14-3-3 isoforms and phosphomimicking substitutions of the threonine residue. Consequently, local H⁺ influxes and effluxes as well as pH gradients in the pollen tube tip are generated by localized regulation of the H⁺ ATPase activity rather than by heterogeneous localized distribution in the plasma membrane.

Intrinsic neuronal excitability, defined by the balance between input and output signals, is crucial to neural function, and its disruption underlies various neurological diseases. Kv3.1 channels, encoded by KCNC1 , are essential for high-frequency action potential firing. Variants in these channels are associated with several subtypes of epilepsy. We report a patient with developmental regression and epilepsy, meeting Rett syndrome criteria, who carries a KCNC1 variant encoding the S474C substitution in Kv3.1 (Kv3.1 ^S474C ). Electrophysiological and biochemical assays reveal that Kv3.1 ^S474C reduces channel presence in the plasma membrane and is retained in the endoplasmic reticulum (ER). In murine primary cultures expressing Kv3.1 ^S474C , we observed reduced neuronal firing frequency and exclusion of the channel from the axon initial segment (AIS). Consistently, we found a decreased firing frequency using a conductance-based computational neuronal model. In summary, this study identifies a novel link between a KCNC1 variant and Rett syndrome, highlighting the importance of S474 residue in Kv3.1 channel trafficking and function in neurons. Summary: This study identifies and characterizes a novel KCNC1 variant associated with classical Rett syndrome. This variant disrupts endoplasmic reticulum (ER) to Golgi trafficking of the Kv3.1 channels, highlighting the variant’s potential role in altered neuronal excitability and neurodevelopmental disorders.

Intrinsic neuronal excitability, defined by the balance between input and output signals, is crucial to neural function, and its disruption underlies various neurological diseases. Kv3.1 channels, encoded by KCNC1 , are essential for high-frequency action potential firing. Variants in these channels are associated with several subtypes of epilepsy. We report a patient with developmental regression and epilepsy, meeting Rett syndrome criteria, who carries a KCNC1 variant encoding the S474C substitution in Kv3.1 (Kv3.1 ^S474C ). Electrophysiological and biochemical assays reveal that Kv3.1 ^S474C reduces channel presence in the plasma membrane and is retained in the endoplasmic reticulum. In murine primary cortical neuron cultures expressing Kv3.1 ^S474C , we observed reduced neuronal firing frequency and exclusion of the channel from the axon initial segment. Consistently, we found a decreased firing frequency using a conductance-based computational neuronal model. In summary, this study identifies a link between a KCNC1 variant and Rett syndrome, highlighting the importance of S474 residue in Kv3.1 channel trafficking and function in neurons.

Dietary factors may influence cognitive aging and Alzheimer’s disease (AD), but observational associations, mechanistic findings, and intervention effects should not be considered equivalent evidence. This critical narrative review examines how dietary patterns, micronutrient adequacy, and metabolic health may modify AD-related vulnerability. A targeted search of PubMed/MEDLINE, Scopus, and Web of Science through April 2026 prioritized systematic reviews, meta-analyses, randomized trials, and prospective cohorts. Mediterranean, Mediterranean–DASH Intervention for Neurodegenerative Delay (MIND), and healthful plant-based dietary patterns have been associated with better cognitive outcomes and lower dementia risk. However, evidence remains predominantly observational, and randomized trials have not consistently demonstrated prevention of cognitive decline. Strict vegan diets have not shown additional protection beyond high-quality plant-based diets and require careful attention to vitamin B12 and overall nutritional adequacy. Ketogenic diets and medium-chain triglycerides may increase cerebral ketone availability, but their cognitive benefits remain inconsistent, and disease modification has not been established. Although vitamin B12, folate, and vitamin D support neural and metabolic functions, correcting deficiency should not be equated with treating AD. Overall, nutrition should be viewed as a contributor to cardiometabolic and neurological resilience and as part of person-centered dementia care, rather than as a stand-alone disease-modifying therapy. Future studies should integrate accurate dietary assessment, objective adherence measures, metabolic phenotyping, AD biomarkers, and clinically meaningful outcomes.