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Conflicts of interest
Newly Identified Mechanisms of APN Resistance Hold Therapeutic Potential
APN, APN Receptors, and APN Cardiovascular Protection
APN Resistance in Cardiovascular Disease
The Molecular Mechanisms of APN Resistance
Concluding Remarks and Future Directions Finally, most recent studies have demonstrated that AdipoR1 is phosphorylated in the failing heart. This receptor phosphorylation results in loss of responsiveness to APN. However, many unanswered questions warrant further investigation. Although Ser7, Thr24, and Thr53 are sensitive to/selective for GRK2 phosphorylation, it remains to be determined which residue’s phosphorylation is responsible for receptor desensitization, and whether one, two, or all three residues must be phosphorylated to maximally block APN signaling remains unknown. This has important implications for the design of a clinically applicable therapeutic. Any effective therapeutic agent must prevent the phosphorylation of residues within the receptor protein leading to its desensitization. Whether the agent must block one, two, or all three amino Forsythoside A residues from alteration must be determined through basic science studies with clear clinical relevancy. Obtaining a clear answer to these questions is scientifically important, enhancing our understanding of APN receptor biology, but may also help us develop specific interventions that selectively enhance APN metabolic and/or anti-inflammatory signaling under non-diabetic and/or diabetic conditions. It is well known that AdipoR1 phosphorylation inhibits APN signaling, albeit via unknown molecular mechanisms. Multiple possibilities exist. First, AdipoR1 is internalized in a ligand-independent fashion [77]. AdipoR1 phosphorylation may increase its internalization, thereby blocking its function, similar to β-AR. Second, multiple AdipoR1 intracellular binding proteins, including APPL1, nCDase, Cav3, activated protein kinase C1 (RACK1), and protein kinase CK2 β subunit (CK2β) have been identified. The interactions between these proteins and AdipoR1 are respectively required in APN-mediated metabolic regulation, anti-inflammation, and cellular protection 78, 79, 80. The binding of APPL2 to AdipoR1, by contrast, inhibits APN signaling. AdipoR1 phosphorylation may plausibly alter one or more of these interactions in a manner blocking APN function. Third, APN exerts an antioxidative function in a cAMP-initiated, PKA-dependent fashion [81]. As PAQR5, 7, and 8 interact with G proteins [82], it is possible that G proteins may influence AdipoR1 signaling. Similar to β-AR, phosphorylation of AdipoR1 may alter its affinity, recruiting β-arrestin [83] and thereby blocking AdipoR1 function. As the ultimate goal of experimental investigation is to advance our understanding of human disease and enhance human health, it is of great importance to determine whether pharmacologic or genetic interventions capable of blocking AdipoR1 phosphorylation will reestablish the cardiometabolic regulatory, anti-inflammatory, and cardioprotective effects of APN in the failing heart, particularly in diabetic conditions. Abbreviation list
Introduction Japanese quail is an interesting research model, used extensively for photoperiodic studies. Reports indicate that quail respond to long days which are gonado-stimulatory (photosensitive) in general, followed by the development of relative photorefractoriness [1]. It can also reproduce under short day conditions. Longer time is required for the bird to prepare for breeding under short day conditions (scotorefractoriness) after the initial phase of scotosensitivity (gonadal suppression under short days) [2]. Thus, it displays both the phenomenon of photo/scotosensitivity and photo/scotorefractoriness [3,4]. Photoperiod potentially influences the body weight via modulating the homeostasis between energy intake and energy expenditure [5,6]. Boon et al. [6] clearly demonstrated that longer photoperiods result in increased weight gains through influencing the balance between energy intake and energy expenditure levels.