Regulation of sinoatrial funny channels by cyclic nucleotides: From adrenaline and IK2 to direct binding of ligands to protein subunits.

The funny current, and the HCN channels that form it, are affected by the direct binding of cyclic nucleotides. Binding of these second messengers causes a depolarizing shift of the activation curve, which leads to greater availability of current at physiological membrane voltages. This review outlines a brief history on this regulation and provides some evidence that other cyclic nucleotides, especially cGMP, may be important for the regulation of the funny channel in the heart. Current understanding of the molecular mechanism of cyclic nucleotide regulation is also presented, which includes the notions that full and partial agonism occur as a consequence of negatively cooperative binding. Knowledge gaps, including a potential role of cyclic nucleotide-regulation of the funny current under pathophysiological conditions, are included. The work highlighted here is in dedication to Dario DiFrancesco on his retirement.

The Impact of Psychiatric Disorder Diagnosis on Motivation to Quit and Stage of Change Among Patients at a Hospital-Based Outpatient Smoking Cessation Clinic.

OBJECTIVE: Smoking is among the greatest international public health concerns, causing excessive levels of preventable premature death, disability, and economic costs. The prevalence of tobacco use among people with psychiatric disorders (PDs) remains persistently high relative to the general population, highlighting the need to improve smoking cessation (SC) strategies in this group. We aimed to assess the associations between having a PD and baseline motivation to quit (MtQ) smoking and Prochaska's stage of change (SoC), two clinically important metrics linked to SC outcomes. Methods: This retrospective chart review included patients who completed a baseline visit at a hospital-based outpatient SC clinic (N = 896). Multivariate hierarchical logistic and linear regression models were developed to assess variables associated with MtQ (importance and confidence in quitting) and SoC, primarily PD category (externalizing, internalizing, externalizing/internalizing, psychotic or no PD) and secondarily, demographics, physical health history, and tobacco use/dependence metrics. Results: The variables negatively associated with MtQ were female sex (p = .011), older age (p = .038), deriving income from social assistance (p < .001), and age at smoking initiation (p = .005), whereas ≥ 1 quit attempt in the past year predicted higher MtQ (p < .0001). Being in the preparative/action SoC (versus the pre-contemplative/contemplative) was associated with income from social assistance (OR 0.39, p = .001), more daily cigarettes smoked (OR 0.98, p = .005) and ≥ 1 past-year quit attempt (OR 1.69, p = .013). Conclusions: Having a PD was not associated with either MtQ or SoC. Deriving income from social assistance predicted lower MtQ and SoC. Having made ≥ 1 quit attempt in the past year was associated with higher MtQ and SoC. Our study suggests that people with PDs are as motivated to quit smoking and ready for change as people without PDs, and smoking cessation efforts should be amplified in this group to address the disproportionately high level of tobacco use, especially because having at least one quit attempt may enhance MtQ and SoC.