New Insights into the Mechanism of Permeation through Large Channels

Komarov, Alexander G.; Deng, Defeng; Craigen, William J.; Colombini, Marco

doi:10.1529/biophysj.105.070037

Cited by 43 publications

(31 citation statements)

References 44 publications

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“…A possible mechanism is the dimerization of the VDAC (40,51). The Ca 2ϩ -dependent patterns described here may be modulated in the cell by the generation of electrical potential across the OMM (52); by the pH (53); by the interaction of VDAC with other ions and small molecules, including NADH (54), purine nucleotides (55)(56)(57), and superoxide (25); and with a range of proteins that have been listed above. Along the line of a commonly proposed model, the VDAC interacts with the adenine nucleotide translocase and cyclophilin D to form the PTP, which is primarily regulated by [Ca 2ϩ ] m .…”

Section: Discussionmentioning

confidence: 93%

Ca2+-dependent Control of the Permeability Properties of the Mitochondrial Outer Membrane and Voltage-dependent Anion-selective Channel (VDAC)

Báthori

Csordás

Garcı́a-Pérez

et al. 2006

Journal of Biological Chemistry

198

142

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Cell function depends on the distribution of cytosolic and mitochondrial factors across the outer mitochondrial membrane (OMM). Passage of metabolites through the OMM has been attributed to the voltage-dependent anion-selective channel (VDAC),2؉ may facilitate the cation and ATP transport across the OMM. Thus, the VDAC gating is dependent on the physiological concentrations of cations, allowing the OMM to control the passage of ions and some small molecules. The OMM barrier is likely to decrease during the calcium signal.Mitochondria were recognized first as the main source of cellular ATP production, but over recent years their role has also been established in many aspects of cell physiology and pathophysiology (1). For example, to regulate cell survival, mitochondria retain proteins that induce apoptosis upon release to the cytosol (2-5) and participate in calcium signaling by rapidly accumulating and releasing Ca 2ϩ (6 -9). Tight control of the transport of small molecules and ions across the inner mitochondrial membrane (IMM) 2 has been established, whereas, based on early studies of isolated mitochondria, the outer mitochondrial membrane (OMM) was perceived to form a barrier only for large molecules.The voltage-dependent anion-selective channel (VDAC)/mitochondrial porin is the most abundant protein of the OMM. When reconstituted in artificial membrane systems, such as liposomes and planar bilayer membranes (black lipid membrane (BLM)), the VDAC commonly appears as a large channel. At low potentials (Ͻ30 mV), the VDAC was found to be mostly fully open (ϳ4.5-nanosiemens conductance in 1 M KCl) and weakly anion-selective, whereas at high potentials, the VDAC showed a switch to cationic selectivity and closed to approximately half of the original conductance (classical "closed" states) (10 -13). Since the molecular cut-off of the VDAC is Ͼ3,000 Da in the fully open state, the common belief was that the OMM is freely permeable to small molecules and ions. However, during the past decade, several lines of evidence raised questions about the large size pore-forming activity of the VDAC in natural membranes and the consequent high permeability of the OMM (14). Patch clamp measurements of OMM fractions and intracellular patch clamping of native mitochondria did not show high conductance channel activity (15, 16) unless ionic strength or [Ca 2ϩ ] was elevated to supraphysiological levels (17). Within a cell, the OMM may form a barrier against the transport of some small molecules (e.g. ADP (18, 19)). Furthermore, in certain apoptosis models, the OMM permeability has been shown to be restricted for metabolites (20). Recently, selective permeabilization of the OMM by tBid, a proapoptotic protein (21), and by overexpression of VDAC (22) permeability could limit rapid Ca 2ϩ uptake to the mitochondria during physiological calcium signals. Furthermore, using targeted enhanced yellow fluorescence protein, lower pH was recorded in the mitochondrial intermembrane space (IMS) than that in the cytosol (23). A possible expl...

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Section: Discussionmentioning

confidence: 93%

Ca2+-dependent Control of the Permeability Properties of the Mitochondrial Outer Membrane and Voltage-dependent Anion-selective Channel (VDAC)

Báthori

Csordás

Garcı́a-Pérez

et al. 2006

Journal of Biological Chemistry

198

142

View full text Add to dashboard Cite

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“…In brief, the OMM fraction was extracted with 1.2% digitonin, and the remaining mixture of matrix and IMM was purified through 0.5% Lubrol, where the matrix fraction remained in solution after centrifugation, and the IMM fraction formed the pellet (28). Proteins with a nonspecific association or loose association with the membranes were removed by incubation with proteinase K. Fractions were then processed for Western blotting using the indicated antibodies.…”

Section: Methodsmentioning

confidence: 99%

Inner Mitochondrial Translocase Tim50 Interacts with 3β-Hydroxysteroid Dehydrogenase Type 2 to Regulate Adrenal and Gonadal Steroidogenesis

Pawlak

Prasad

Thomas

et al. 2011

Journal of Biological Chemistry

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Background:The role of mitochondrial translocases in steroid hormone synthesis is investigated. Results: Expression of inner mitochondrial translocase Tim50 is essential for DHEA and androstenedione synthesis. Conclusion: Tim50 interacts with 3␤HSD2 for steroid hormone synthesis. Significance: During steroidogenesis, the flexibility of 3␤HSD2 is essential to coordinate interaction between Tim50 and Tom22.

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“…Genetic removal of a set of positive charges within the pore resulted in a channel that was cation rather than anion selective, and that had only about half the unitary conductance. In spite of this change, the permeability to ATP was unaltered (Komarov et al, 2005) -one would have expected the permeability to ATP to decrease with the change in charge selectivity. It was concluded that ATP flux through VDAC channels is determined by specific sites within the channel, not by the overall charge density of the pore, which is reflected in the cation/anion selectivity.…”

Section: Specific Affinities In Other Large Poresmentioning

confidence: 99%

Connexin channel permeability to cytoplasmic molecules

Harris¹

2007

Progress in Biophysics and Molecular Biology

414

346

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Connexin channels are known to be permeable to a variety of cytoplasmic molecules. The first observation of second messenger junctional permeability, made ∼30 years ago, sparked broad interest in gap junction channels as mediators of intercellular molecular signaling. Since then, much has been learned about the diversity of connexin channels with regard to isoform diversity, tissue and developmental distribution, modes of channel regulation, assembly and expression, biochemical modification and permeability, all of which appear to be dynamically regulated. This information has expanded the potential roles of connexin channels in development, physiology and disease, and made their elucidation much more complex -30 years ago such an orchestra of junctional dynamics was unanticipated. Only recently, however, have investigators been able to directly address, in this more complex framework, the key issue: What specific biological molecules, second messengers and others, are able to permeate the various types of connexin channels, and how well? An important related issue, given the ever-growing list of connexin-related pathologies, is how these permeabilities are altered by disease-causing connexin mutations. Together, many studies show that a variety of cytoplasmic molecules can permeate the different types of connexin channels. A few studies reveal differences in permeation by different molecules through a particular type of connexin channel, and differences in permeation by a particular molecule through different types of connexin channels. This article describes and evaluates the various methods used to obtain these data, presents an annotated compilation of the results, and discusses the findings in the context of what can be inferred about mechanism of selectivity and potential relevance to signaling. The data strongly suggest that highly specific interactions take place between connexin pores and specific biological molecular permeants, and that those interactions determine which cytoplasmic molecules can permeate and how well. At this time, the nature of those interactions is unclear. One hopes that with more detailed permeability and structural information, the specific molecular mechanisms of the selectivity can be elucidated.

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New Insights into the Mechanism of Permeation through Large Channels

Cited by 43 publications

References 44 publications

Ca2+-dependent Control of the Permeability Properties of the Mitochondrial Outer Membrane and Voltage-dependent Anion-selective Channel (VDAC)

Ca2+-dependent Control of the Permeability Properties of the Mitochondrial Outer Membrane and Voltage-dependent Anion-selective Channel (VDAC)

Inner Mitochondrial Translocase Tim50 Interacts with 3β-Hydroxysteroid Dehydrogenase Type 2 to Regulate Adrenal and Gonadal Steroidogenesis

Connexin channel permeability to cytoplasmic molecules

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