Specific role of neuronal nitric-oxide synthase when tethered to the plasma membrane calcium pump in regulating the beta-adrenergic signal in the myocardium

The cardiac neuronal nitric-oxide synthase (nNOS) has been described as a modulator of cardiac contractility. We have demonstrated previously that isoform 4b of the sarcolemmal calcium pump (PMCA4b) binds to nNOS in the heart and that this complex regulates beta-adrenergic signal transmission in vivo. Here, we investigated whether the nNOS-PMCA4b complex serves as a specific signaling modulator in the heart. PMCA4b transgenic mice (PMCA4b-TG) showed a significant reduction in nNOS and total NOS activities as well as in cGMP levels in the heart compared with their wild type (WT) littermates. In contrast, PMCA4b-TG hearts showed an elevation in cAMP levels compared with the WT. Adult cardiomyocytes isolated from PMCA4b-TG mice demonstrated a 3-fold increase in Ser(16) phospholamban (PLB) phosphorylation as well as Ser(22) and Ser(23) cardiac troponin I (cTnI) phosphorylation at base line compared with the WT. In addition, the relative induction of PLB phosphorylation and cTnI phosphorylation following isoproterenol treatment was severely reduced in PMCA4b-TG myocytes, explaining the blunted physiological response to the beta-adrenergic stimulation. In keeping with the data from the transgenic animals, neonatal rat cardiomyocytes overexpressing PMCA4b showed a significant reduction in nitric oxide and cGMP levels. This was accompanied by an increase in cAMP levels, which led to an increase in both PLB and cTnI phosphorylation at base line. Elevated cAMP levels were likely due to the modulation of cardiac phosphodiesterase, which determined the balance between cGMP and cAMP following PMCA4b overexpression. In conclusion, these results showed that the nNOS-PMCA4b complex regulates contractility via cAMP and phosphorylation of both PLB and cTnI.

Implications of divergences in Adult Protection legislation

Purpose – The purpose of this paper is to explore the similarities and differences of legal responses to older adults who may be at risk of harm or abuse in the UK, Ireland, Australia and the USA.
Design/methodology/approach – The authors draw upon a review of elder abuse and adult protection undertaken on behalf of the commissioner for older people in Northern Ireland. This paper focusses on the desk top mapping of the different legal approaches and draws upon wider literature to frame the discussion of the relative strengths and weaknesses of the different legal responses.
Findings – Arguments exist both for and against each legal approach. Differences in defining the scope and powers of adult protection legislation in the UK and internationally are highlighted.
Research limitations/implications – This review was undertaken in late 2013; while the authors have updated the mapping to take account of subsequent changes, some statutory guidance is not yet available. While the expertise of a group of experienced professionals in the field of adult safeguarding was utilized,
it was not feasible to employ a formal survey or consensus model.
Practical implications – Some countries have already introduced APL and others are considering doing so. The potential advantages and challenges of introducing APL are highlighted.
Social implications – The introduction of legislation may give professionals increased powers to prevent and reduce abuse of adults, but this would also change the dynamic of relationships within families and between families and professionals.
Originality/value – This paper provides an accessible discussion of APL across the UK and internationally
which to date has been lacking from the literature.