My field of research is molecular biophysics of mechanosensory transduction processes in living cells. The focus of my research is on the structure and function of mechanosensitive channels, which form a class of integral membrane proteins converting mechanical stimuli into electrochemical cellular signals.
Piezo channels are a ubiquitously expressed, principal type of molecular force sensor in eukaryot... more Piezo channels are a ubiquitously expressed, principal type of molecular force sensor in eukaryotes. They enable cells to decode a myriad of physical stimuli and are essential components of numerous mechanosensory processes. Central to their physiological role is the ability to change conformation in response to mechanical force. Here we discuss the evolutionary origin of Piezo in relation to other MS channels in addition to the force that gates Piezo channels. In particular, we discuss whether Piezo channels are inherently mechanosensitive in accordance with the force-from-lipid paradigm which has been firmly established for bacterial MS channels and two-pore domain K+ (K2P) channels. We also discuss the evidence supporting a reliance on or direct interaction with structural scaffold proteins of the cytoskeleton and extracellular matrix according to the force-from-filament principle. In doing so, we explain the false dichotomy that these distinctions represent. We also discuss the possible unifying models that shed light on channel mechanosensitivity at the molecular level.
Although the ion channels of vertebrates, and larger invertebrates have been the focus of channel... more Although the ion channels of vertebrates, and larger invertebrates have been the focus of channel research in the past and at the present, some studies of the channels of microbes have been made. The microbial channels were found to have many similar and a few different features from those of the metazoan channels.
Filopodia are ubiquitous membrane projections that play crucial role in guiding cell migration on... more Filopodia are ubiquitous membrane projections that play crucial role in guiding cell migration on rigid substrates and through extracellular matrix by utilizing yet unknown mechanosensing molecular pathways. As recent studies show that Ca2+channels localized to filopodia play an important role in regulation of their formation and since some Ca2+channels are known to possess mechanosensing properties, activity of filopodial Ca2+channels might be tightly interlinked with the filopodia mechanosensing function. We tested this hypothesis by monitoring changes in the intra-filopodial Ca2+level in response to application of stretching force to individual filopodia of several cell types. It has been found that stretching forces of tens of pN strongly promote Ca2+influx into filopodia, causing persistent Ca2+oscillations that last for minutes even after the force is released. Most of the known mechanosensitive Ca2+channels, such as Piezo 1, Piezo 2 and TRPV4, were found to be dispensable for...
In this review, we present our current understanding of peripartum cardiomyopathy (PPCM) based on... more In this review, we present our current understanding of peripartum cardiomyopathy (PPCM) based on reports of the incidence, diagnosis and current treatment options. We summarise opinions on whether PPCM is triggered by vascular and/or hormonal causes and examine the influence of comorbidities such as preeclampsia. Two articles published in 2021 strongly support the hypothesis that PPCM may be a familial disease. Using large cohorts of PPCM patients, they summarised the available genomic DNA sequence data that are expressed in human cardiomyocytes. While PPCM is considered a disease predominately affecting the left ventricle, there are data to suggest that some cases also involve right ventricular failure. Finally, we conclude that there is sufficient evidence to warrant an RNAseq investigation and that this would be most informative if performed at the cardiomyocytes level rather than analysing genomic DNA from the peripheral circulation. Given the rarity of PPCM, the combined resou...
Cellular processes including adhesion, migration, and differentiation are governed by the distinc... more Cellular processes including adhesion, migration, and differentiation are governed by the distinct mechanical properties of each cell. Importantly, the mechanical properties of individual cells can vary depending on local physical and biochemical cues in a time‐dependent manner resulting in significant inter‐cell heterogeneity. While several different methods have been developed to interrogate the mechanical properties of single cells, throughput to capture this heterogeneity remains an issue. Here, single‐cell, high‐throughput characterization of adherent cells is demonstrated using acoustic force spectroscopy (AFS). AFS works by simultaneously, acoustically driving tens to hundreds of silica beads attached to cells away from the cell surface, allowing the user to measure the stiffness of adherent cells under multiple experimental conditions. It is shown that cells undergo marked changes in viscoelasticity as a function of temperature, by altering the temperature within the AFS mic...
Proceedings of the National Academy of Sciences, 2021
Significance Mechanosensitive (MS) channels play a key role in the physiology of organisms from b... more Significance Mechanosensitive (MS) channels play a key role in the physiology of organisms from bacteria to man. Many prokaryotic and eukaryotic MS channels respond to membrane tension. Here, we show that cyclodextrin (CD)–mediated lipid removal induces membrane tension that activates not only the mechanosensitive channel of small conductance but the structurally unrelated mechanosensitive channel of large conductance, which gates at almost lytic membrane tensions. This finding suggests that for both functional and structural studies, provided that sufficient CD is added and enough lipids are removed, any tension-sensitive ion channel can be activated. Moreover, CDs may also prove useful for the in vitro study of other membrane proteins that are sensitive to mechanical forces.
RationaleGq-coupled receptors are thought to play a critical role in the induction of left ventri... more RationaleGq-coupled receptors are thought to play a critical role in the induction of left ventricular hypertrophy (LVH) secondary to pressure overload, although mechano-sensitive channel activation by a variety of mechanisms has also been proposed, and the relative importance of calcineurin- and calmodulin kinase II (CaMKII)-dependent hypertrophic pathways remains controversial.ObjectiveTo determine the mechanisms regulating the induction of LVH in response to mechanical pressure overload.Methods and ResultsTransgenic mice with cardiac-targeted inhibition of Gq-coupled receptors (GqI mice) and their non-transgenic littermates (NTL) were subjected to neurohumoral stimulation (continuous, subcutaneous angiotensin II (AngII) infusion for 14 days) or mechanical pressure overload (transverse aortic arch constriction (TAC) for 21 days) to induce LVH. Candidate signalling pathway activation was examined. As expected, LVH observed in NTL mice with AngII infusion was attenuated in heterozyg...
Mechanoelectrical transduction is a cellular signalling pathway where physical stimuli are conver... more Mechanoelectrical transduction is a cellular signalling pathway where physical stimuli are converted into electro-chemical signals by mechanically activated ion channels. We describe here the presence of mechanically activated currents in melanoma cells that are dependent on TMEM87a, which we have renamed Elkin1. Heterologous expression of this protein in PIEZO1-deficient cells, that exhibit no baseline mechanosensitivity, is sufficient to reconstitute mechanically activated currents. Melanoma cells lacking functional Elkin1 exhibit defective mechanoelectrical transduction, decreased motility and increased dissociation from organotypic spheroids. By analysing cell adhesion properties, we demonstrate that Elkin1 deletion is associated with increased cell-substrate adhesion and decreased homotypic cell-cell adhesion strength. We therefore conclude that Elkin1 supports a PIEZO1-independent mechanoelectrical transduction pathway and modulates cellular adhesions and regulates melanoma ce...
Mechanosensitive ion channels are membrane gated pores which are activated by mechanical stimuli.... more Mechanosensitive ion channels are membrane gated pores which are activated by mechanical stimuli. The focus of this study is on Piezo1, a newly discovered, large, mammalian, mechanosensitive ion channel, which has been linked to diseases such as dehydrated hereditary stomatocytosis (Xerocytosis) and lymphatic dysplasia. Here we utilize an established in-vitro artificial bilayer system to interrogate single Piezo1 channel activity. The droplet-hydrogel bilayer (DHB) system uniquely allows the simultaneous recording of electrical activity and fluorescence imaging of labelled protein. We successfully reconstituted fluorescently labelled Piezo1 ion channels in DHBs and verified activity using electrophysiology in the same system. We demonstrate successful insertion and activation of hPiezo1-GFP in bilayers of varying composition. Furthermore, we compare the Piezo1 bilayer reconstitution with measurements of insertion and activation of KcsA channels to reproduce conductances reported in ...
Piezo channels are a ubiquitously expressed, principal type of molecular force sensor in eukaryot... more Piezo channels are a ubiquitously expressed, principal type of molecular force sensor in eukaryotes. They enable cells to decode a myriad of physical stimuli and are essential components of numerous mechanosensory processes. Central to their physiological role is the ability to change conformation in response to mechanical force. Here we discuss the evolutionary origin of Piezo in relation to other MS channels in addition to the force that gates Piezo channels. In particular, we discuss whether Piezo channels are inherently mechanosensitive in accordance with the force-from-lipid paradigm which has been firmly established for bacterial MS channels and two-pore domain K+ (K2P) channels. We also discuss the evidence supporting a reliance on or direct interaction with structural scaffold proteins of the cytoskeleton and extracellular matrix according to the force-from-filament principle. In doing so, we explain the false dichotomy that these distinctions represent. We also discuss the possible unifying models that shed light on channel mechanosensitivity at the molecular level.
Although the ion channels of vertebrates, and larger invertebrates have been the focus of channel... more Although the ion channels of vertebrates, and larger invertebrates have been the focus of channel research in the past and at the present, some studies of the channels of microbes have been made. The microbial channels were found to have many similar and a few different features from those of the metazoan channels.
Filopodia are ubiquitous membrane projections that play crucial role in guiding cell migration on... more Filopodia are ubiquitous membrane projections that play crucial role in guiding cell migration on rigid substrates and through extracellular matrix by utilizing yet unknown mechanosensing molecular pathways. As recent studies show that Ca2+channels localized to filopodia play an important role in regulation of their formation and since some Ca2+channels are known to possess mechanosensing properties, activity of filopodial Ca2+channels might be tightly interlinked with the filopodia mechanosensing function. We tested this hypothesis by monitoring changes in the intra-filopodial Ca2+level in response to application of stretching force to individual filopodia of several cell types. It has been found that stretching forces of tens of pN strongly promote Ca2+influx into filopodia, causing persistent Ca2+oscillations that last for minutes even after the force is released. Most of the known mechanosensitive Ca2+channels, such as Piezo 1, Piezo 2 and TRPV4, were found to be dispensable for...
In this review, we present our current understanding of peripartum cardiomyopathy (PPCM) based on... more In this review, we present our current understanding of peripartum cardiomyopathy (PPCM) based on reports of the incidence, diagnosis and current treatment options. We summarise opinions on whether PPCM is triggered by vascular and/or hormonal causes and examine the influence of comorbidities such as preeclampsia. Two articles published in 2021 strongly support the hypothesis that PPCM may be a familial disease. Using large cohorts of PPCM patients, they summarised the available genomic DNA sequence data that are expressed in human cardiomyocytes. While PPCM is considered a disease predominately affecting the left ventricle, there are data to suggest that some cases also involve right ventricular failure. Finally, we conclude that there is sufficient evidence to warrant an RNAseq investigation and that this would be most informative if performed at the cardiomyocytes level rather than analysing genomic DNA from the peripheral circulation. Given the rarity of PPCM, the combined resou...
Cellular processes including adhesion, migration, and differentiation are governed by the distinc... more Cellular processes including adhesion, migration, and differentiation are governed by the distinct mechanical properties of each cell. Importantly, the mechanical properties of individual cells can vary depending on local physical and biochemical cues in a time‐dependent manner resulting in significant inter‐cell heterogeneity. While several different methods have been developed to interrogate the mechanical properties of single cells, throughput to capture this heterogeneity remains an issue. Here, single‐cell, high‐throughput characterization of adherent cells is demonstrated using acoustic force spectroscopy (AFS). AFS works by simultaneously, acoustically driving tens to hundreds of silica beads attached to cells away from the cell surface, allowing the user to measure the stiffness of adherent cells under multiple experimental conditions. It is shown that cells undergo marked changes in viscoelasticity as a function of temperature, by altering the temperature within the AFS mic...
Proceedings of the National Academy of Sciences, 2021
Significance Mechanosensitive (MS) channels play a key role in the physiology of organisms from b... more Significance Mechanosensitive (MS) channels play a key role in the physiology of organisms from bacteria to man. Many prokaryotic and eukaryotic MS channels respond to membrane tension. Here, we show that cyclodextrin (CD)–mediated lipid removal induces membrane tension that activates not only the mechanosensitive channel of small conductance but the structurally unrelated mechanosensitive channel of large conductance, which gates at almost lytic membrane tensions. This finding suggests that for both functional and structural studies, provided that sufficient CD is added and enough lipids are removed, any tension-sensitive ion channel can be activated. Moreover, CDs may also prove useful for the in vitro study of other membrane proteins that are sensitive to mechanical forces.
RationaleGq-coupled receptors are thought to play a critical role in the induction of left ventri... more RationaleGq-coupled receptors are thought to play a critical role in the induction of left ventricular hypertrophy (LVH) secondary to pressure overload, although mechano-sensitive channel activation by a variety of mechanisms has also been proposed, and the relative importance of calcineurin- and calmodulin kinase II (CaMKII)-dependent hypertrophic pathways remains controversial.ObjectiveTo determine the mechanisms regulating the induction of LVH in response to mechanical pressure overload.Methods and ResultsTransgenic mice with cardiac-targeted inhibition of Gq-coupled receptors (GqI mice) and their non-transgenic littermates (NTL) were subjected to neurohumoral stimulation (continuous, subcutaneous angiotensin II (AngII) infusion for 14 days) or mechanical pressure overload (transverse aortic arch constriction (TAC) for 21 days) to induce LVH. Candidate signalling pathway activation was examined. As expected, LVH observed in NTL mice with AngII infusion was attenuated in heterozyg...
Mechanoelectrical transduction is a cellular signalling pathway where physical stimuli are conver... more Mechanoelectrical transduction is a cellular signalling pathway where physical stimuli are converted into electro-chemical signals by mechanically activated ion channels. We describe here the presence of mechanically activated currents in melanoma cells that are dependent on TMEM87a, which we have renamed Elkin1. Heterologous expression of this protein in PIEZO1-deficient cells, that exhibit no baseline mechanosensitivity, is sufficient to reconstitute mechanically activated currents. Melanoma cells lacking functional Elkin1 exhibit defective mechanoelectrical transduction, decreased motility and increased dissociation from organotypic spheroids. By analysing cell adhesion properties, we demonstrate that Elkin1 deletion is associated with increased cell-substrate adhesion and decreased homotypic cell-cell adhesion strength. We therefore conclude that Elkin1 supports a PIEZO1-independent mechanoelectrical transduction pathway and modulates cellular adhesions and regulates melanoma ce...
Mechanosensitive ion channels are membrane gated pores which are activated by mechanical stimuli.... more Mechanosensitive ion channels are membrane gated pores which are activated by mechanical stimuli. The focus of this study is on Piezo1, a newly discovered, large, mammalian, mechanosensitive ion channel, which has been linked to diseases such as dehydrated hereditary stomatocytosis (Xerocytosis) and lymphatic dysplasia. Here we utilize an established in-vitro artificial bilayer system to interrogate single Piezo1 channel activity. The droplet-hydrogel bilayer (DHB) system uniquely allows the simultaneous recording of electrical activity and fluorescence imaging of labelled protein. We successfully reconstituted fluorescently labelled Piezo1 ion channels in DHBs and verified activity using electrophysiology in the same system. We demonstrate successful insertion and activation of hPiezo1-GFP in bilayers of varying composition. Furthermore, we compare the Piezo1 bilayer reconstitution with measurements of insertion and activation of KcsA channels to reproduce conductances reported in ...
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Papers by Boris Martinac