Stimulation of cardiac β-adrenergic receptors (β-AR) activates both the Gs- and Gi-coupled signaling cascades, including the phosphoinositide 3 kinase (PI3K) pathway, that have important physiological implications. Multiple isoforms of PI3K exist in the heart. The goals of this study were to examine the intracellular signaling pathways linking β-AR to PI3K and to identify the PI3K isoform mediating this transactivation in a cardiac context. Acute β-AR stimulation with isoproterenol resulted in increased tyrosine kinase-associated PI3K activity and phosphorylation of Akt and p70S6K in H9c2 cardiomyocytes. Cotreatment with ICI-118,551, but not CGP-20712, abolished the increase in PI3K activity, suggesting a β2-AR-mediated event. PI3K activation was also abrogated by cotreatment with pertussis toxin, 4-amino-5-(4-chlorophenyl)-7-( t-butyl)pyrazolol[3,4-d]pyrimidine (PP2, a selective Src-family tyrosine kinases inhibitor), or AG-1296 [selective platelet-derived growth factor receptor (PDGFR) inhibitor] but not with an inhibitor for protein kinase A, protein kinase C, Ras, adenylyl cyclase, epidermal growth factor receptor, or insulin-like growth factor-1 receptor. β-AR stimulation induced an increase in tyrosine phosphorylation of PDGFR, which was abolished by inhibition of Src either by PP2 or small interfering RNA. Moreover, H9c2 cardiomyocytes stably transfected with a vector expressing a Gβγ sequestrant peptide derived from the COOH-terminus of β-AR kinase-1 failed to activate PI3K after β-AR stimulation, suggesting Gβγ is required for the transactivation. Furthermore, acute β-AR stimulation in vivo resulted in increases in PDGFR-associated PI3K and PI3Kα isoform activities but not the activities of other isoforms (PI3Kβ, -δ, -γ) in adult mouse heart. Taken together, these data provide in vitro and in vivo evidence for a novel mechanism of β-AR-mediated transactivation of cardiac PI3Kα via sequential involvement of Gαi/Gβγ, Src, and PDGFR.
Purpose of review
Summarize the effects of opioids on sleep including sleep architecture, sleep disordered breathing (SDB) and restless legs syndrome.
Recent findings
Opioids are associated with the development of central sleep apnea (CSA) and ataxic breathing. Recent reports suggest that adaptive servo-ventilation may be an effective treatment for CSA associated with opioids.
Summary
Opioids have multiple effects on sleep, sleep architecture and SDB. Although originally described with methadone use, most commonly used opioids have also been shown to affect sleep. In patients on chronic methadone, sleep architecture changes include decreases in N3 and REM sleep. However, in patients with chronic nonmalignant pain, opioids improve sleep quality and sleep time. Opioids, generally at a morphine equivalent dose more than 100 mg/day, are associated with an increased incidence of CSA and ataxic breathing as well as obstructive sleep apnea. Other risk factors may include concomitant use of other medications such as antidepressants, gabapentinoids and benzodiazepines. Opioid-induced CSA can be potentially treated with adaptive servo-ventilation. Finally, opioids are a potential therapeutic option for restless legs syndrome unresponsive to dopamine agonists and other medications. However, use in patients with restless legs syndrome should proceed with caution, taking into account the risk for dependence and development of SDB.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.