Annual Review of Physiology

All mammals and birds must develop effective strategies to cope with reduced oxygen availability. These animals achieve tolerance to acute and chronic hypoxia by (a) reductions in metabolism, (b) the prevention of cellular injury, and (c) the maintenance of functional integrity. Failure to meet any one of these tasks is detrimental. Birds and mammals accomplish this triple task through a highly coordinated, systems-level reconfiguration involving the partial shutdown of some but not all organs. This reconfiguration is achieved through a similarly complex reconfiguration at the cellular and molecular levels. Reconfiguration at these various levels depends on numerous factors that include the environment, the degree of hypoxic stress, and developmental, behavioral, and ecological conditions. Although common molecular strategies exist, the cellular and molecular changes in any given cell are very diverse. Some cells remain metabolically active, whereas others shut down or rely on anaerobic metabolism. This cellular shutdown is temporarily regulated, and during hypoxic exposure, active cellular networks must continue to control vital functions. The challenge for future research is to explore the cellular mechanisms and conditions that transform an organ or a cellular network into a hypometabolic state, without loss of functional integrity. Much can be learned in this respect from nature: Diving, burrowing, and hibernating animals living in diverse environments are masters of adaptation and can teach us how to deal with hypoxia, an issue of great clinical significance.

Mitochondrial fatty acid β-oxidation (FAO) is the major pathway for the degradation of fatty acids and is essential for maintaining energy homeostasis in the human body. Fatty acids are a crucial energy source in the postabsorptive and fasted states when glucose supply is limiting. But even when glucose is abundantly available, FAO is a main energy source for the heart, skeletal muscle, and kidney. A series of enzymes, transporters, and other facilitating proteins are involved in FAO. Recessively inherited defects are known for most of the genes encoding these proteins. The clinical presentation of these disorders may include hypoketotic hypoglycemia, (cardio)myopathy, arrhythmia, and rhabdomyolysis and illustrates the importance of FAO during fasting and in hepatic and (cardio)muscular function. In this review, we present the current state of knowledge on the biochemistry and physiological functions of FAO and discuss the pathophysiological processes associated with FAO disorders.

Maintenance of a homeostatic body core temperature is a critical brain function accomplished by a central neural network. This orchestrates a complex behavioral and autonomic repertoire in response to environmental temperature challenges or declining energy homeostasis and in support of immune responses and many behavioral states. This review summarizes the anatomical, neurotransmitter, and functional relationships within the central neural network that controls the principal thermoeffectors: cutaneous vasoconstriction regulating heat loss and shivering and brown adipose tissue for heat production. The core thermoregulatory network regulating these thermoeffectors consists of parallel but distinct central efferent pathways that share a common peripheral thermal sensory input. Delineating the neural circuit mechanism underlying central thermoregulation provides a useful platform for exploring its functional organization, elucidating the molecular underpinnings of its neuronal interactions, and discovering novel therapeutic approaches to modulating body temperature and energy homeostasis.

The Na,K-ATPase is the membrane “pump” that generates the Na⁺ and K⁺ gradients across the plasma membrane that drives many physiological processes. This enzyme is highly sensitive to inhibition by cardiotonic steroids, most notably the digitalis/ouabain class of compounds, which have been used for centuries to treat congestive heart failure and arrhythmias. The amino acids that constitute the ouabain-binding site are highly conserved across the evolutionary spectrum. This could be fortuitous or could result from this site being conserved because it has an important biological function. New physiological approaches using genetically engineered mice are being used to define the biological significance of the “receptor function” of the Na,K-ATPase and its regulation by potential endogenous cardiotonic steroid-like compounds. These studies extend the reach of earlier studies involving the biochemical purification of endogenous regulatory ligands.

▪ Abstract  In Drosophila photoreceptors, the light-sensitive current is mediated downstream of phospholipase C by TRP (transient receptor potential) channels. Recent evidence suggests that Drosophila TRP channels are activated by diacylglycerol (DAG) or its metabolites (polyunsaturated fatty acids), possibly in combination with the reduction in phosphatidyl inositol 4,5 bisphosphate (PIP₂). Consistent with this view, diacylglycerol kinase is identified as a key enzyme required for response termination. Signaling is critically dependent upon efficient PIP₂ synthesis; mutants of this pathway in combination with genetically targeted PIP₂ reporters provide unique insights into the kinetics and regulation of PIP₂ turnover. Recent evidence indicates that a growing number of mammalian TRP homologues are also regulated by lipid messengers, including DAG, arachidonic acid, and PIP₂.

Vesicle exocytosis releases content to mediate many biological events, including synaptic transmission essential for brain functions. Following exocytosis, endocytosis is initiated to retrieve exocytosed vesicles within seconds to minutes. Decades of studies in secretory cells reveal three exocytosis modes coupled to three endocytosis modes: (a) full-collapse fusion, in which vesicles collapse into the plasma membrane, followed by classical endocytosis involving membrane invagination and vesicle reformation; (b) kiss-and-run, in which the fusion pore opens and closes; and (c) compound exocytosis, which involves exocytosis of giant vesicles formed via vesicle-vesicle fusion, followed by bulk endocytosis that retrieves giant vesicles. Here we review these exo- and endocytosis modes and their roles in regulating quantal size and synaptic strength, generating synaptic plasticity, maintaining exocytosis, and clearing release sites for vesicle replenishment. Furthermore, we highlight recent progress in understanding how vesicle endocytosis is initiated and is thus coupled to exocytosis. The emerging model is that calcium influx via voltage-dependent calcium channels at the calcium microdomain triggers endocytosis and controls endocytosis rate; calmodulin and synaptotagmin are the calcium sensors; and the exocytosis machinery, including SNARE proteins (synaptobrevin, SNAP25, and syntaxin), is needed to coinitiate endocytosis, likely to control the amount of endocytosis.