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Highlights From The Literature

Edited by Christopher D. Verrico

Offspring from mothers fed a "junk food" diet in pregnancy and lactation exhibit exacerbated adiposity that is more pronounced in females. Bayol SA, Simbi BH, Bertrand JA, Stickland NC. J Physiol 586: 3219–3230, 2008.[Abstract/Free Full Text]

Nominated by Allan Vaaga
vaa{at}steno.dk

Question: How does eating "junk food" during pregnancy and/or lactation affect the metabolism of offspring?

Background: During the past 20 years, there has been an increase in obesity in the United States. Although there are many factors involved in obesity, a diet rich in fat, sugar, and salt (junk food) is thought to be at least a factor in this dramatic increase. Recently, the Strickland laboratory published a study that described how rodents fed a junk food diet during pregnancy were more likely to give birth to offspring that overate and had a preference for junk food. In this study, they wanted to determine whether the effects of diet during pregnancy and breastfeeding could be a potential factor in the development of obesity and associated metabolic disruptions in offspring.

Observations: Pregnant rats were fed a balanced diet or had an open-access junk food diet. The offspring of the mothers fed junk food diets had lower birth weights and raised levels of cholesterol as well as higher levels of triglycerides; this was maintained in the offspring from mothers switched to healthy food from junk food while suckling. Offspring weaned on to junk food all overate, regardless of what the mother had eaten during pregnancy and suckling. The group of offspring who were in the junk food diet group and were from a parent given junk both while pregnant and while suckling ate the most of all three groups. Interestingly, the offspring who were weaned on to a healthy diet alone were not subsequently found to overeat, even when the mothers had been fed junk food throughout pregnancy and suckling.

Significance: These results suggest that mothers who eat an unhealthy diet during pregnancy may be putting their children at risk of developing obesity and raised levels of cholesterol and blood sugar. This is of concern because obesity increases the risk of many diseases and health conditions, including hypertension, osteoarthritis, dyslipidemia, Type 2 diabetes, and the list goes on. Although this study may not provide the evidence to support this conclusion in humans, it does support the idea that, during pregnancy, it is important that mothers are aware that what they eat may affect their offspring.

Mechanism of Ca²⁺ disruption in Alzheimer’s disease by presenilin regulation of InsP₃ receptor channel gating. Cheung KH, Shineman D, Müller M, Cárdenas C, Mei L, Yang J, Tomita T, Iwatsubo T, Lee VM, Foskett JK. Neuron 58: 871–883, 2008.[CrossRef][Web of Science][Medline]

Nominated by Tullio Pozzantullio
pozzan{at}unipd.it

Question: Do the abnormalities in Ca²⁺ signaling observed in Alzheimer’s disease (AD) contribute to the pathogenesis of the disease?

Background: Ca²⁺ release from intracellular storage compartments is a ubiquitous signaling mechanism that regulates a diverse array of normal and pathophysiological processes in cells. Although the "amyloid hypothesis" of AD is perhaps the best known, accumulating evidence suggests that perturbations in intracellular Ca²⁺ signaling may have a central role in the pathogenesis of the disease. In fact, presenilins (PSs) are the major cause of familial AD and have been associated with abnormalities in Ca²⁺ signaling. In addition, fibroblast lines derived from patients with AD are also known to have altered Ca²⁺ signaling.

Observations: Using electrophysiology techniques, along with biochemical and functional assays, Cheung et al. determined that PSs in the endoplasmic reticulum (ER) interact with the inositol 1,4,5-trisphosphate receptor (InsP₃R) calcium release channel. This resulted in excessive Ca²⁺ release from the ER, which stimulates amyloid beta (Aβ) processing.

Significance: These findings suggest a novel mechanism by which mutant presenilins can cause perturbations in intraneuronal calcium signaling, which is linked with enhanced Aβ production. This is in contrast to an earlier study that suggested that exaggerated calcium signaling induced by mutant PS comes from overloaded stores of calcium within the ER. Nevertheless, these data provide molecular insights into the "Ca²⁺ dysregulation hypothesis" of AD pathogenesis, which could lead to novel therapeutic approaches that selectively target these Ca²⁺ channels.

The crystal structure of a sodium galactose transporter reveals mechanistic insights into Na⁺/sugar symport. Faham S, Watanabe A, Besserer GM, Cascio D, Specht A, Hirayama BA, Wright EM, Abramson J. Science 321: 810–814, 2008.[Abstract/Free Full Text]

Nominated by Baruch Kanner
kannerb{at}cc.huji.ac.il

Question: What can the crystal structure of a sodium galactose transporter reveal about the molecular mechanism of Na⁺/glucose cotransporter proteins (SGLTs)?

Background: When carbohydrates are consumed, they are metabolized into simple sugars, which are then transported into cells by a SGLT. These secondary membrane transporter proteins are known as solute sodium symporters (SSS), a large family of proteins that couple the transport of nutrients into the cell with the transport of sodium out of the cell. Available data suggest that all secondary membrane transporters operate via a common alternating-access mechanism. However, the molecular mechanism of this symporter has remained unclear.

Observations: Faham et al. determined that the sodium galactose symporter from Vibrio parahaemolyticus (vSGLT) consists of 14 transmembrane helices with the amino and carboxy termini facing outward and an inward-facing galactose binding site. Interestingly, the core structure is topologically similar to the core structure of LeuT, a member of the neurotransmitters sodium symporter (NSS) family, which does not share a significant similarity in amino-acid sequence. Utilizing computer modeling to exploit these similiarities, they determined the first atomic level evidence for the mechanism underlying transport of glucose and neurotransmitters into cells.

Significance: These results represents a major step forward toward understanding the mechanism of solute transport across membranes. By comparing the two aforementioned structures, the authors provide the first direct evidence for alternating access in membrane transporters. This suggests that, despite a lack of significant sequence identity, these two families of transporter proteins are evolutionarily related and may share a similar transport mechanism. Members of this protein family play crucial roles in human health, and pharmaceutical companies already have extensive clinical trials underway to evaluate the use of these inhibitors in various disorders. These findings should enhance the ability to rationally design these drugs.

AMP-activated protein kinase phosphorylates and desensitizes smooth muscle myosin light chain kinase. Horman S, Morel N, Vertommen D, Hussain N, Neumann D, Beauloye C, El Najjar N, Forcet C, Viollet B, Walsh MP, Hue L, Rider MH. J Biol Chem 283: 18505–18512, 2008.[Abstract/Free Full Text]

Nominated by Ulrich Pohl

Question: Does AMP-activated protein kinase (AMPK) have a role in smooth muscle contraction?

Background: AMPK is expressed in a number of tissues and consists of three subunits that play a role in cellular energy homeostasis, acting as an energy sensor. AMPK is regulated by intracellular Ca²⁺ and AMP concentrations. Similarly, intracellular Ca²⁺ also regulates smooth muscle contraction, which occurs by Ca²⁺ binding to calmodulin (CaM), leading to activation of smooth muscle myosin light chain kinase (smMLCK). Although smMLCK has two phosphorylation sites by which its activity is modulated, it is unknown whether smMLCK is a substrate for AMPK.

Observations: Horman et al. determined that MLCK is a substrate of AMPK, with the phosphorylation site of MLCK located in the CaM-binding domain. Phosphorylation of MLCK by AMPK decreased the affinity of MLCK for Ca²⁺/CaM. They also found that stimulation of aortic smooth muscle cells led to Ca²⁺-dependent AMPK activation, which they could inhibit by blocking CaMKKβ.

Significance: These findings suggest that the role of AMPK is not solely to sense energy. Instead, AMPK appears to also play a role in vascular smooth muscle, where it can cause vasodilation by phosphorylating MLCK and altering its sensitivity to Ca²⁺/CaM. Adiponectin is a circulating cytokine secreted by adipose tissue that can act via AMPK. Because adiponectin is reduced in hypertension and obesity, these findings may help to explain the association between the two disorders.

Unexpected structural and functional consequences of the R33Q homozygous mutation in cardiac calsequestrin: a complex arrhythmogenic cascade in a knock in mouse model. Rizzi N, Liu N, Napolitano C, Nori A, Turcato F, Colombi B, Bicciato S, Arcelli D, Spedito A, Scelsi M, Villani L, Esposito G, Boncompagni S, Protasi F, Volpe P, Priori SG. Circ Res 103: 298–306, 2008.[Abstract/Free Full Text]

Nominated by Litsa Kraniaslitsa
kranias{at}uc.edu

Question: Does a mutation in the cardiac calsequestrin gene (CASQ2) result in the rare autosomal recessive form of catecholaminergic polymorphic ventricular tachycardia (CPVT)?

Background: CPVT is an inherited heart rhythm disorder characterized by arrhythmias and caused by a mutation in the cardiac ryanodine receptor (RyR). Following results from human studies, which found that 50% of CPVT patients carry mutations in RyR2, Priori and colleagues developed a mouse knock-in model with a RyR2 mutation that developed bidirectional and polymorphic VT. Other findings in mouse models with mutations in the cardiac calsequestrin gene (CASQ2) led to the hypothesis that a reduction in CASQ2 activates a compensatory increase in calreticulin. In the current report, they characterize a point mutation in CASQ2 to further understand CPVT.

Observations: Utilizing a novel knock-in mouse carrier of a CASQ2 point mutation (R33Q), they sought to closely mimic the clinical phenotype of CPVT patients who are highly symptomatic and known to have this mutation. Both the mouse and myocytes from the mouse displayed a set of abnormalities, which are indicative of CPVT.

Significance: The findings in this report suggest that CASQ2 reduction is one of the common pathogenic mechanisms of autosomal recessive CPVT. Additionally, the authors suggest that different missense mutations may be characterized by specific functional abnormalities of CASQ2, leading to variable compensatory responses. These findings help to elucidate the complex pathogenesis of recessive CPVT.

The mechanism of a neurotransmitter:sodium symporter: inward release of Na⁺ and substrate is triggered by substrate in a second binding site. Shi L, Quick M, Zhao Y, Weinstein H, Javitch JA. Mol Cell 30: 667–677, 2008.[CrossRef][Web of Science][Medline]

Nominated by Baruch Kanner
kannerb{at}cc.huji.ac.il

Question: How are substrates translocated by neurotransmitter:sodium symporters?

Background: Neurotransmitter transport systems are responsible for the release, re-uptake, and recycling of neurotransmitters at synapses. In addition to regulating neurotransmission, neurotransmitter:sodium symporters (NSS) are targets for psychostimulants, anti-depressants, and other drugs. Previous research from Javitch et al. revealed that, without Na⁺, the NSS has an inward-facing confirmation. In contrast, in the presence of Na⁺, conformational changes take place that result in an outward-facing confirmation. In this report, they elucidate how these conformational changes might drive transport.

Observations: Initially, Shi et al. performed computer simulations to reveal the path of the transported molecules into cells. Next, they used steered molecular dynamics and the crystal structure of a bacterial transporter to explore the substrate translocation pathway and validate these predictions. They identified a secondary extracellular substrate binding site, which suggests that two sodium ions bind and stabilize the transporter molecule for the correct positioning of the two messenger molecules. Thus the second binding causes changes in the transporter, allowing one of the two sodium molecules to move inward and then release the bound messenger and its sodium partner into the cell.

Significance: The primary finding was that two binding sites on the transporter need to be filled in order for transport to be driven across the cell membrane. Although crystallography experiments lead to the identification of a structural form of the molecule, these experiments and computations identified how this form changes and thereby adds an understanding of the functional role of the different forms that the molecule must adopt to accomplish transport activity. Although these findings will likely be most valuable to developing more effective therapies for psychiatric diseases, including addiction, it may also lead to the development of new therapies for dopamine-neurotransmitter disorders such as Parkinson’s disease.

Fluid flow induces mechanosensitive ATP release, calcium signaling and Cl^– transport in biliary epithelial cells through a PKC-dependent pathway. Woo K, Dutta AK, Patel V, Kresge C, Feranchak AP. J Physiol 586: 2779–2798, 2008.[Abstract/Free Full Text]

Nominated by Hugh Matthews
hrm1{at}cam.ac.uk

Question: How is ATP release form biliary epithelial cells induced?

Background: ATP plays an important role as a signaling molecule, although the physiological stimulus for ATP release from cholangiocytes (the epithelial cells of the bile duct) is unknown. ATP release from other epithelial cells is induced by physical or mechanical forces resulting in stretch, deformation, or some other perturbation of the plasma membrane. Similar to these epithelial cells, biliary epithelial cells are also exposed to physical forces, such as membrane tension due to swelling. However, whether this regulates cholangiocyte secretory events is unknown.

Observations: Using a multidisciplinary approach, Woo et al. investigate how fluid flow is coupled to transepithelial ion transport in biliary epithelia. The authors propose a model whereby flow stimulates PKC-dependent ATP release. Released ATP in turn activates puringeric receptors, leading to an increase in intracellular calcium and the stimulation of Cl^– secretion via Ca²⁺-activated Cl^– channels.

Significance: These findings suggest that mechanosensitive ATP release may be a key regulator of biliary secretion. However, it remains to be seen whether this mechanism of coupling fluid Ca²⁺ flow to transepithelial ion transport might serve as an important regulatory mechanism in other epithelial tissues. Nonetheless, further exploring these findings may provide novel strategies for treating cholestatic liver disorders.

Massive Ca-induced membrane fusion and phospholipid changes triggered by reverse Na/Ca exchange in BHK fibroblasts Yaradanakul A, Wang TM, Lariccia V, Lin MJ, Shen C, Liu X, and Hilgemann DW. J Gen Physiol 132: 29–50, 2008.[Abstract/Free Full Text]

Ca-dependent nonsecretory vesicle fusion in a secretory cell. Wang TM, Hilgemann DW. J Gen Physiol 132: 51–65, 2008.[Abstract/Free Full Text]

Nominated by ?

Question: How does the Ca²⁺-activated fusion process occur in various cell types?

Background: Fibroblasts are cells that synthesize and maintain the extracellular matrix of tissues. As such, they play a critical role in wound healing, which employs Ca²⁺-triggered membrane fusion of secretory granules (SGs). Both SNAREs and synaptotagmins are implicated in the fusion process, including the sensing of increased Ca²⁺. Phospholipase C (PLC) substrates bind to and modulate the function of synaptotagmins, which controls membrane fusion in neurons. This, and other findings implicating PLCs in membrane fusion, prompted further exploration into the potential role of PLCs in the Ca²⁺-induced membrane fusion process in fibroblasts. Non-SG fusion also occurs in both secretory and nonsecretory cell lines, which suggests that it may have a role in cell survival. However, the sources of membrane involved and the underlying mechanisms of this fusion process remain unknown. This phenomenon was explored in the second manuscript.

Observations: In the first report, Yaradanakul et al. performed whole-cell patch-clamp experiments with baby hamster kidney (BHK) cells expressing the Na⁺/Ca²⁺ exchanger NCX1. By using a high intracellular concentration of Na⁺ and a high extracellular Ca²⁺ concentration, they were able to induce a massive influx of Ca²⁺, which triggered a pronounced capacitance increase. Next, they performed studies to determine the role of phosphoinositides in this and determined that Ca²⁺ influx activates PI(4,5)P₂ breakdown. However, phosphoinositide metabolism was found to be neither sufficient nor necessary for the membrane-fusion response. In the second manuscript, Wang and Hilgemann determined that non-SG fusion differs substantially from SG fusion, in that vesicle fusion in rat basophilic leukemia (RBL) cells appears to occur independently of phosphoinositide metabolism. In addition, treating the cells with tetanus toxin (TeTx) resulted in complete inhibition of the capacitance response.

Significance: In contrast to what has been reported for hormone release from neuroendocrine cells, where PI(4,5)P₂ appears to have a role in the priming as well as the fusion, the first report suggests that the regulation of fusion of SGs from BHK cells is unique. The activation of PLCs, which occurs in parallel to membrane fusion in response to increased cytoplasmic Ca²⁺, is not only unrelated to the fusion process in fibroblasts but does not modulate it either. The results of the second paper suggest that, in contrast to other cell types, exocytosis of RBL vesicles is mediated by a TeTx-sensitive vesicle-associated membrane protein (VAMP) family member, such as synaptobrevin-2 or cellubrevin. This is in line with recent findings that suggest different sub-populations of vesicles undergoing regulated exocytosis in mast cells may involve different VAMP family members.

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