GABAA receptor associated protein (GABARAP) modulates TRPV1 expression and channel function and desensitization.

Transient receptor potential vanilloid (TRPV1) transduces noxious chemical and physical stimuli in high-threshold nociceptors. The pivotal role of TRPV1 in the physiopathology of pain transduction has thrust the identification and characterization of interacting partners that modulate its cellular function. Here, we report that TRPV1 associates with gamma-amino butyric acid A-type (GABA(A)) receptor associated protein (GABARAP) in HEK293 cells and in neurons from dorsal root ganglia coexpressing both proteins. At variance with controls, GABARAP augmented TRPV1 expression in cotransfected cells and stimulated surface receptor clustering. Functionally, GABARAP expression attenuated voltage and capsaicin sensitivity of TRPV1 in the presence of extracellular calcium. Furthermore, the presence of the anchor protein GABARAP notably lengthened the kinetics of vanilloid-induced tachyphylaxia. Notably, the presence of GABARAP selectively increased the interaction of tubulin with the C-terminal domain of TRPV1. Disruption of tubulin cytoskeleton with nocodazole reduced capsaicin-evoked currents in cells expressing TRPV1 and GABARAP, without affecting the kinetics of vanilloid-induced desensitization. Taken together, these findings indicate that GABARAP is an important component of the TRPV1 signaling complex that contributes to increase the channel expression, to traffic and cluster it on the plasma membrane, and to modulate its functional activity at the level of channel gating and desensitization.

Differential contribution of SNARE-dependent exocytosis to inflammatory potentiation of TRPV1 in nociceptors.

Potentiation of the pain-integrator ion channel transient receptor potential vanilloid type 1 (TRPV1) underlies thermal hyperalgesia mediated by a variety of proinflammatory factors. Two complementary mechanisms of TRPV1 inflammatory sensitization have been proposed, namely a decrease of its activation threshold and an increment of its surface expression in nociceptors. Here we investigated the involvement of regulated exocytosis to the inflammatory sensitization of TRPV1 in rat neonatal dorsal root ganglion neurons by proalgesic agents. The contribution of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-dependent exocytosis was evaluated using a small peptide patterned after the synaptosomal-associated protein of 25 kDa (SNAP-25) protein that acts as a specific and potent inhibitor of neuronal exocytosis. We found that TRPV1 sensitization mediated by nerve growth factor, ATP, and IGF-I was accompanied by a higher channel expression in the neuronal plasma membrane, which was prevented by blockade of regulated exocytosis. In contrast, TRPV1 sensitization caused by bradykinin, IL-1beta, and artemin was insensitive to inhibition of SNARE-dependent vesicular fusion and was not due to an increase in TRPV1 surface expression. Therefore, it appears that some, but not all, proinflammatory agents sensitize rat nociceptors by promoting the recruitment of TRPV1 channels to the neuronal surface. These findings support the tenet that SNARE complex-mediated exocytosis of TRPV1 may be a valid therapeutic target to treat inflammatory pain.

Muscle loss: The new malnutrition challenge in clinical practice.

Recent definitions of malnutrition include low muscle mass within its diagnostic criteria. In fact, malnutrition is one of the main risk factors of skeletal muscle loss contributing to the onset of sarcopenia. However, differences in the screening and diagnosis of skeletal muscle loss, especially as a result of malnutrition in clinical and community settings, still occur mainly as techniques and thresholds used vary in clinical practice. The objectives of this position paper are firstly to emphasize the link between skeletal muscle loss and malnutrition-related conditions and secondly to raise awareness for the timely identification of loss of skeletal muscle mass and function in high risk populations. Thirdly to recognize the need to implement appropriate nutritional strategies for prevention and treatment of skeletal muscle loss and malnutrition across the healthcare continuum. Malnutrition needs to be addressed clinically as a muscle-related disorder and clinicians should integrate nutritional assessment with muscle mass measurements for optimal evaluation of these two interrelated entities to tailor interventions appropriately. The design of monitoring/evaluation and discharge plans need to include multimodal interventions with nutrition and physical exercise that are key to preserve patient's muscle mass and function in clinical and community settings.

Role of Oral Nutritional Supplements Enriched with ß-Hydroxy-ß-Methylbutyrate in Maintaining Muscle Function and Improving Clinical Outcomes in Various Clinical Settings.

Aging and disease-related malnutrition are well associated with loss of muscle mass and function. Muscle mass loss may lead to increased health complications and associated increase in health care costs, especially in hospitalized individuals. High protein oral nutritional supplements enriched with ß-hydroxy-ß-methylbutyrate (HP-ONS+HMB) have been suggested to provide benefits such as improving body composition, maintaining muscle mass and function and even decreasing mortality rates. The present review aimed to examine current evidence on the effect of HP-ONS+HMB on muscle-related clinical outcomes both in community and peri-hospitalization patients. Overall, current evidence suggests that therapeutic nutrition such as HP-ONS+HMB seems to be a promising tool to mitigate the decline in muscle mass and preserve muscle function, especially during hospital rehabilitation and recovery.

Synthesis of a new fluorescent conjugated polymer microsphere for chemical sensing in aqueous media.

A novel conjugated polymer microsphere of high value for fluorescent sensing in aqueous media has been synthesized. New conjugated polymers were functionalized in the side chain with imidazole moieties (recognition element) and a terminal double bond (covalently linked to an organic matrix) through a post-functionalization strategy.