A high affinity switch for cAMP in the HCN pacemaker channels.

Binding of cAMP to Hyperpolarization activated cyclic nucleotide gated (HCN) channels facilitates pore opening. It is unclear why the isolated cyclic nucleotide binding domain (CNBD) displays in vitro lower affinity for cAMP than the full-length channel in patch experiments. Here we show that HCN are endowed with an affinity switch for cAMP. Alpha helices D and E, downstream of the cyclic nucleotide binding domain (CNBD), bind to and stabilize the holo CNBD in a high affinity state. These helices increase by 30-fold cAMP efficacy and affinity measured in patch clamp and ITC, respectively. We further show that helices D and E regulate affinity by interacting with helix C of the CNBD, similarly to the regulatory protein TRIP8b. Our results uncover an intramolecular mechanism whereby changes in binding affinity, rather than changes in cAMP concentration, can modulate HCN channels, adding another layer to the complex regulation of their activity.

Studies on health in elderly observation centers (abbreviated from Italian: COSA): a multidimensional evaluation (MDE) of an elderly population frequenting a diurnal center in Catania.

The worldwide progressive aging of the population forces us to reconsider the strategies of evaluation the effects of the geriatric "tsunami" on the health politics. The present study on the COSA (abbreviated from the Italian name: "Centro Osservazione Salute Anziani") has the aim to investigate the effects of a new form called Specialistic Geriatric Assistance on the already existing geriatric services in our territory, like UVG (Unità Valutazione Geriatrica), ADI (Assistenza Domiciliare Integrata), MMG (Medici di Medicina Generale). The present preliminary studies were carried out a group of elderly people frequenting the elderly day center "Villa Angela" located in Catania. We enrolled 42 subjects, 29 females and 13 males, in the age-range of 65-89 years (mean=73.6 years). An evaluation protocol was used for the participants, having two parts. The first part was a general one performing an accurate anamnestic examination, while the second part evaluated the cognitive and affective spheres, and the levels of autonomy and autosufficiency. The data obtained show that that the elderly population of the daily center "Villa Angela" in Catania is affected by numerous pathologies and comorbidities, which all increase the total risk of disabilities. The subjects use a high number of medicines (sometimes more than 10), which is not always justified by the pathologies found in them. Considering the functional profiles of the patients, the sanitary services offered to them are appropriate, because almost all of the elderly people were autonomous and autosufficient, having still adequate physical performances. The higher cognitive performance seemed to be reduced in more than 50% of the patients, showing almost always a slight or moderate deterioration. The depressive state measured by the GDS seemed to reach the deflection of joy of life 54.8%, while the established depression was detected in 12%. These results emphasize the importance of the functional psychogeriatric screening, which is able to reveal an early diagnosis of depression in the geriatric ages. For this, and many other motifs, we believe that these preliminary examinations suggest to organize at least one COSA available to our elderly people.