HCN channels: Structure, cellular regulation and physiological function

Hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels belong to the superfamily of voltage-gated pore loop channels. HCN channels are unique among vertebrate voltage-gated ion channels, in that they have a reverse voltage-dependence that leads to activation upon hyperpolarization. In addition, voltage-dependent opening of these channels is directly regulated by the binding of cAMP. HCN channels are encoded by four genes (HCN1–4) and are widely expressed throughout the heart and the central nervous system. The current flowing through HCN channels, designated I_h or I_f, plays a key role in the control of cardiac and neuronal rhythmicity (“pacemaker current”). In addition, I_h contributes to several other neuronal processes, including determination of resting membrane potential, dendritic integration and synaptic transmission. In this review we give an overview on structure, function and regulation of HCN channels. Particular emphasis will be laid on the complex roles of these channels for neuronal function and cardiac rhythmicity. Received 22 August 2008; received after revision 22 September 2008; accepted 24 September 2008     

A Smurf1 tale: function and regulation of an ubiquitin ligase in multiple cellular networks

Since being discovered and intensively studied for over a decade, Smad ubiquitylation regulatory factor-1 (Smurf1) has been linked with several important biological pathways, including the bone morphogenetic protein pathway, the non-canonical Wnt pathway, and the mitogen-activated protein kinase pathway. Multiple functions of this ubiquitin ligase have been discovered in cell growth and morphogenesis, cell migration, cell polarity, and autophagy. Smurf1 is related to physiological manifestations in terms of age-dependent deficiency in bone formation and invasion of tumor cells. Smurf1-knockout mice have a significant phenotype in the skeletal system and considerable manifestations during embryonic development and neural outgrowth. In depth studying of Smurf1 will help us to understand the etiopathological mechanisms of related disorders. Here, we will summarize historical and recent studies on Smurf1, and discuss the E3 ligase-dependent and -independent functions of Smurf1. Moreover, intracellular regulations of Smurf1 and related physiological phenotypes will be described in this review.     

RGD在整合素中的作用及纤粘蛋白介导的生物学过程

整合素直接参与细胞与细胞质的相互作用,控制细胞的分化、形态发生、增殖和迁徙。整合素直接参与细胞与细胞质的相互作用受到细胞粘附分子整合素家族的调节,以增强它们的粘附功能。整合素受体功能被认为是细胞行为的关键调节器。在再生性血管中选择性表达的许多分子中,整合素在肿瘤靶向方面显示出了特别的希望。SaiKi和其合作者报告．肿瘤再生血管受到整合素和含有精氨酸-甘氨酸-天冬氨酸（RGD）序列的细胞质蛋白的相互作用而受到抑制。在再生性心血管形成中研究最多之一的靶向决定簇是αvβ3整合素。研究表明αvβ3和αvβ5整合素更能调节血管再生内皮细胞,并且这些整合素受到抗体的抑制,环RGD肽和RGD多肽类似物能干扰新血管的形成。本文意在概括一下RGD在整合素中的作用及纤粘蛋白介导的生物过程。     

Modulation of chemokine receptor activity through dimerization and crosstalk

Chemokines are small, secreted proteins that bind to the chemokine receptor subfamily of class A G protein-coupled receptors. Collectively, these receptor-ligand pairs are responsible for diverse physiological responses including immune cell trafficking, development and mitogenic signaling, both in the context of homeostasis and disease. However, chemokines and their receptors are not isolated entities, but instead function in complex networks involving homo- and heterodimer formation as well as crosstalk with other signaling complexes. Here the functional consequences of chemokine receptor activity, from the perspective of both direct physical associations with other receptors and indirect crosstalk with orthogonal signaling pathways, are reviewed. Modulation of chemokine receptor activity through these mechanisms has significant implications in physiological and pathological processes, as well as drug discovery and drug efficacy. The integration of signals downstream of chemokine and other receptors will be key to understanding how cells fine-tune their response to a variety of stimuli, including therapeutics. Received 19 October 2008; received after revision 7 November 2008; accepted 11 November 2008 C. L. Salanga, M. O’Hayre: These authors contributed equally.     

Hsp90 regulation of mitochondrial protein folding: from organelle integrity to cellular homeostasis

Although essential for energy production and cell fate decisions, the mechanisms that govern protein homeostasis, or proteostasis, in mitochondria are only recently beginning to emerge. Fresh experimental evidence has uncovered a role of molecular chaperones of the heat shock protein 90 (Hsp90) family in overseeing the protein folding environment in mitochondria. Initially implicated in protection against cell death, there is now evidence that Hsp90-directed protein quality control in mitochondria connects to hosts of cellular homeostatic networks that become prominently exploited in human cancer.     

Regulation of end-binding protein EB1 in the control of microtubule dynamics

The regulation of microtubule dynamics is critical to ensure essential cell functions, such as proper segregation of chromosomes during mitosis or cell polarity and migration. End-binding protein 1 (EB1) is a plus-end-tracking protein (+TIP) that accumulates at growing microtubule ends and plays a pivotal role in the regulation of microtubule dynamics. EB1 autonomously binds an extended tubulin-GTP/GDP-Pi structure at growing microtubule ends and acts as a molecular scaffold that recruits a large number of regulatory +TIPs through interaction with CAP-Gly or SxIP motifs. While extensive studies have focused on the structure of EB1-interacting site at microtubule ends and its role as a molecular platform, the mechanisms involved in the negative regulation of EB1 have only started to emerge and remain poorly understood. In this review, we summarize recent studies showing that EB1 association with MT ends is regulated by post-translational modifications and affected by microtubule-targeting agents. We also present recent findings that structural MAPs, that have no tip-tracking activity, physically interact with EB1 to prevent its accumulation at microtubule plus ends. These observations point out a novel concept of “endogenous EB1 antagonists” and emphasize the importance of finely regulating EB1 function at growing microtubule ends.     

Inferential processes in the construction of scenarios

The process of scenario construction is not yet well understood. Procedures appeal to the ‘disciplined intuition’ of experts. From a psychological perspective, however, generating scenarios represents a most difficult cognitive task. Two cognitive functions involved in this task are discussed: forward inferences and backward inferences. Whereas forward inferences explore the implications of given options and help to identify potential consequences, backward inferences explore the implications of given goals and help identify potential options. The first process leads to an exploratory scenario, the second to an anticipatory scenario. It is argued that the two approaches, applied to the same problem, result in different scenarios, i.e. scenarios that differ in their elements, their structures, their ranges and their ‘holes’. A bi-directional construction method is suggested that balances the drawbacks implied in using one cognitive strategy only (e.g. forward inference) by using complementarily the other strategy (e.g. backward inference). In contrast to other methods proposed in the literature, this method is theoretically derived and can be tested empirically.     

Utilization of the pH-stat in the study of cellular metabolism

Riassunto È stata studiata la possibilità di seguire con un titolatore automatico impiegato come pH-stat l'andamento della respirazione e della glicolisi di cellule sopravviventi. I valori ottenuti sono in accordo con quelli descritti nella letteratura.Rispetto al metodo manometrico sono segnalati alcuni vantaggi quali la rapidità delle determinazioni, la possibilità di variare più parametri sperimentali nel corso dell'esperienza nonchè la facilità di prelievo di materiale durante l'esperimento.     

The role of the nuclear envelope in cellular organization

Over the last years it has become evident that the nuclear envelope (NE) is more than a passive membrane barrier that separates the nucleus from the cytoplasm. The NE not only controls the trafficking of macromolecules between the nucleoplasm and the cytosol, but also provides anchoring sites for chromosomes and cytoskeleton to the nuclear periphery. Targeting of chromatin to the NE might actually be part of gene expression regulation in eukaryotes. Mutations in certain NE proteins are associated with a diversity of human diseases, including muscular dystrophy, neuropathy, lipodistrophy, torsion dystonia and the premature aging condition progeria. Despite the importance of the NE for cell division and differentiation, relatively little is known about its biogenesis and its role in human diseases. It is our goal to provide a comprehensive view of the NE and to discuss possible implications of NE-associated changes for gene expression, chromatin organization and signal transduction. Received 8 August 2005; received after revision 13 October 2005; accepted 13 October 2005