Several theories have proposed possible functions of adult neurogenesis in learning processes on a systems level, such as the avoidance of catastrophic interference and the encoding of temporal and contextual information, and in emotional behavior. Under the assumption of such functionality of new neurons, the question arises: what are the consequences of adult hippocampal neurogenesis beyond the temporally immediate computational benefit? What might provide the evolutionary advantage of maintaining neurogenesis in the dentate gyrus but almost nowhere else? I propose that over the course of life, activity-dependently regulated adult neurogenesis reveals its true significance in the retained ability for lasting and cumulative network adaptations. The hippocampal precursor cells that generate new neurons with their particular acute function represent a ‘neurogenic reserve’: the potential to remain flexible and plastic in hippocampal learning when the individual is exposed to novelty and complexity.
Results of basic biochemical and physiological research, strongly endorsed by findings in human pathophysiology and genetics, had characterized the glucose phosphorylating enzyme glucokinase as a critical player in normal glucose homeostasis, diabetes mellitus, and hyperinsulinemic hypoglycemia, and identified the enzyme as a promising new drug target. R&D initiated in the early 1990s and directed at this target discovered glucokinase activators (GKAs) as a new class of potentially antidiabetic drugs. GKAs were characterized as nonessential allosteric activators that increase glucose affinity and Vmax of the enzyme, thus stimulating glucose metabolism in glucokinase expressing tissue, of foremost functional significance in the insulin producing pancreatic beta cells and the liver. The results of preclinical testing of GKAs by many pharmaceutical companies demonstrated uniformly high hypoglycemic efficacy in normal and diabetic animals. GKAs were also highly effective in Phase I trials in patients with type 2 diabetes mellitus (T2DM). However, results of a recent Phase II trial were less encouraging because patients developed hyperlipidemia and vascular hypertension, and the drug lost efficacy within several months. This outcome is prompting a reappraisal of the GKA strategy. In this opinion article, the ‘pros and cons’ of the strategy to use these compounds in diabetes management are critically reexamined and suggestions are made that might facilitate progress of GKA R&D that could still result in a novel antidiabetic medicine.
G-protein-coupled receptors (GPCRs) are membrane proteins that convert extracellular information into intracellular signals. They are involved in many biological processes and therefore represent powerful targets to modulate physiological and pathological states. Recent studies have demonstrated that GPCR activity is regulated by several mechanisms. Among these, protein–protein interactions (and in particular interactions with other receptors leading to heteromerization) has been shown to have an important role in modulating GPCR function. This has expanded their repertoire of signaling and added a new level of regulation to their physiological roles. Emerging studies provide evidence for tissue-specific and disease-specific receptor heteromerization. This suggests that heteromers represent novel drug targets for the identification of selective compounds with potentially fewer side-effects.
G-protein-coupled receptors (GPCRs) are the most versatile receptor family as they have the ability to respond to chemically diverse ligands. Despite intensive efforts during the past two decades, there are still more than 100 orphan GPCRs for which endogenous ligands are unknown. Recently, GPR109A, GPR109B and GPR81, which form a GPCR subfamily, have been deorphanized. The physiological ligands of these receptors are the ketone body 3-hydroxy-butyrate, the metabolite 2-hydroxy-propanoate (lactate) as well as the β-oxidation intermediate 3-hydroxy-octanoate. Thus, this receptor subfamily is activated by hydroxy-carboxylic acid ligands which are intermediates of energy metabolism. All three receptors are predominantly expressed in adipocytes and mediate antilipolytic effects. In this article, we propose that the hydroxy-carboxylic acid structure of their endogenous ligands is the defining property of this receptor subfamily and that hydroxy-carboxylic acid receptors function as metabolic sensors which fine-tune the regulation of metabolic pathways.
It is not clear how contracting skeletal muscles mediate the numerous and diverse metabolic and physiological effects that are beneficial for health. Researchers have searched for a muscle-contraction-induced factor – an ‘exercise factor’ – that mediates some of the exercise effects in other tissues such as the liver and adipose tissue. In our search for such a factor, we encountered the cytokine interleukin (IL)-6, which is produced by contracting muscles and released into the blood. We propose that muscle-derived IL-6 meets the criteria of an exercise factor and that such classes of cytokine should be named ‘myokines’. The discovery of contracting muscle as a cytokine-producing organ creates a new paradigm: skeletal muscle as an endocrine organ. By contracting, it stimulates the production and release of myokines that can influence metabolism in tissue and organs. Newly identified myokines and their receptors could serve as targets in the treatment of metabolic disorders and other diseases.
Reports of gene–environment interactions (GxE) between the serotonin transporter gene and stress on risk of depression have generated both excitement and controversy. The controversy persists in part because a mechanistic account of this GxE on serotonergic neurotransmission and risk of depression has been lacking. In this Opinion, we draw on recent discoveries in the functional neuroanatomy of the serotonergic dorsal raphe nucleus (DR) to propose such a mechanistic account. We argue that genetically produced variability in serotonin reuptake during stressor-induced raphe–raphe interactions alters the balance in the amygdala-ventromedial prefrontal cortex (VMPFC)-DR circuitry underlying stressor reactivity and emotion regulation. In particular, the recently characterized stressor-responsive serotonergic interneurons originating from the dorsolateral DR may hold a key to unlocking the GxE mechanism of depression.
The past few years have witnessed intense research into the biological significance of carbon monoxide (CO) as an essential signaling mediator in cells and tissues. To transduce the signal properly, CO must react selectively with functional and structural proteins containing moieties that show preferred reactivity towards this gaseous molecule. This selectivity is exemplified by the interaction of CO with iron- and heme-dependent proteins, although systems containing other transition metals can potentially become a preferential target for CO. Notably, transition metal carbonyls, which carry and liberate CO, are also emerging as a pharmacological tool to mimic the bioactivity of endogenously generated CO. Thus, exploring how CO binding to metal complexes is translated into a cytoprotective function is a challenging task and might open up opportunities for therapeutic applications based on CO delivery.
Operating at the interface of chemical biology, biochemistry, and cell biology, the Baskin Lab develops innovative methods for imaging and probing various classes of lipids and couples these methods to the discovery of novel functions for cellular lipids. Notably, the Baskin Lab has developed a method for imaging the production the signaling lipid phosphatidic acid by phospholipase D enzymes and is applying this method, termed IMPACT, to reveal new biological roles for this lipid second messenger. As well, the Baskin Lab focuses on identifying new roles for inositol-containing phospholipids, or phosphoinositides, in the regulation of developmental and oncogenic signaling by characterizing novel phosphoinositide-binding proteins that act as readers of the membrane bilayer ‘phosphoinositide code’. Collectively, work in the Baskin Lab will elucidate mechanisms of fundamental biological processes and also contribute to the understanding of diseases caused by perturbations in lipid metabolism, including cancer, developmental disorders, and neurological diseases affecting the myelin sheath such as multiple sclerosis.
It is increasingly clear that many metabolic enzymes mistakenly form minor but toxic side-products that must be eliminated to maintain normal fluxes. Collard . show that this is true of two iconic glycolytic enzymes, and that a hitherto somewhat mysterious phosphatase rescues central carbon metabolism from their mistakes.
‘Classic’ enzymes carry out the housekeeping functions of intermediary metabolism. The past decades have seen a steady trickle of reports of several of these enzymes ‘moonlighting’ as RNA-binding proteins. Although evidence for a physiological role for RNA binding is strong in a few individual examples, no systematic concept has been proposed for the overall phenomenon. We suggest that these diverse observations might herald the existence of currently hidden post-transcriptional regulatory networks between intermediary metabolism and gene expression based on RNA, enzyme and metabolite interactions. We briefly summarize the evidence in support of such networks and discuss how current approaches can be employed for systematic analyses and integration into our understanding of cellular biology, given the technical and conceptual advances of the ‘omics’ age.