Remodeling of Kv7.1 and Kv7.5 Expression in Vascular Tumors

Voltage-dependent potassium (Kv) channels contribute to the excitability of nerves and muscles. In addition, Kv participates in several cell functions, including cell cycle progression and proliferation. Kv channel remodeling has been associated with neoplastic cell growth and cancer. Kv7 channels are expressed in blood vessels, and they participate in the maintenance of vascular tone and are implicated in myocyte proliferation. Although evidence links Kv7 remodeling to different types of cancer, its expression in vascular tumors has never been studied. Endothelium-derived vascular neoplasms range from indolent lesions to highly aggressive and metastasizing cancers. Here, we show that Kv7.1 and Kv7.5 are evenly distributed in tunicas as well as the endothelium of healthy veins and arteries. The layered structure of vessels is lost in vascular tumors. By studying eight vascular tumors with different origins and characteristics, we found that Kv7.1 and Kv7.5 expression was changed in vascular cancers. While both channels were generally downregulated, Kv7.5 expression was clearly correlated with neoplastic malignancy. The vascular tumors did not contract; therefore, the role of Kv7 channels is probably related to proliferation rather than controlling vascular tone. Our results identify vascular Kv7 channels as targets for cancer detection and anticancer therapies

Implication of Voltage-Gated Potassium Channels in Neoplastic Cell Proliferation

Altres ajuts: The work carried out by the Molecular Physiology Laboratory was funded by Fondo Europeo de Desarrollo Regional (FEDER). CSN and JC hold fellowships from MINECO and the Fundación Tatiana Pérez de Guzmán el Bueno, respectively.Voltage-gated potassium channels (Kv) are the largest group of ion channels. Kv are involved in controlling the resting potential and action potential duration in the heart and brain. Additionally, these proteins participate in cell cycle progression as well as in several other important features in mammalian cell physiology, such as activation, differentiation, apoptosis, and cell volume control. Therefore, Kv remarkably participate in the cell function by balancing responses. The implication of Kv in physiological and pathophysiological cell growth is the subject of study, as Kv are proposed as therapeutic targets for tumor regression. Though it is widely accepted that Kv channels control proliferation by allowing cell cycle progression, their role is controversial. Kv expression is altered in many cancers, and their participation, as well as their use as tumor markers, is worthy of effort. There is an ever-growing list of Kv that remodel during tumorigenesis. This review focuses on the actual knowledge of Kv channel expression and their relationship with neoplastic proliferation. In this work, we provide an update of what is currently known about these proteins, thereby paving the way for a more precise understanding of the participation of Kv during cancer development

Implication of voltage-gated potassium channels in neoplastic cell proliferation

Voltage-gated potassium channels (Kv) are the largest group of ion channels. Kv are involved in controlling the resting potential and action potential duration in the heart and brain. Additionally, these proteins participate in cell cycle progression as well as in several other important features in mammalian cell physiology, such as activation, differentiation, apoptosis, and cell volume control. Therefore, Kv remarkably participate in the cell function by balancing responses. The implication of Kv in physiological and pathophysiological cell growth is the subject of study, as Kv are proposed as therapeutic targets for tumor regression. Though it is widely accepted that Kv channels control proliferation by allowing cell cycle progression, their role is controversial. Kv expression is altered in many cancers, and their participation, as well as their use as tumor markers, is worthy of effort. There is an ever-growing list of Kv that remodel during tumorigenesis. This review focuses on the actual knowledge of Kv channel expression and their relationship with neoplastic proliferation. In this work, we provide an update of what is currently known about these proteins, thereby paving the way for a more precise understanding of the participation of Kv during cancer development

Biology of the cardiovascular Kv7.1 functional complex

[eng] Voltage gated K+ channels (Kv) are transmembrane proteins that allow the pass-thorugh of potassium ions, regulating the electrochemical gradient of the cell membrane. This way, they modulate several physiological processes, such as proliferation, migration or cell volume. Of particular interest in this dissertation is their role in excitable cells, were they control several key functions. The relevance of this ion channels is evidenced when mutations or alterations in the proper functioning of Kv channels causes severe pathologies, including cardiovascular or neuronal diseases, autoimmune affectations or cancer. Kv channels are tetramers of 4 α subunits with 6 transmembrane segments each one, that associate to form the pore and generate a functional channel. The wide functional diversity of currents is due to a vast number of modulations: heterotetramerization of α subunits, splicing variants, post-translational modifications or the association with regulatory subunits. The last ones include KCNE family, which co-assemble with the channel and modulate its electrophysiological, pharmacological or physiological properties. Kv7.1 associates with KCNE1 in cardiomyocytes to generate IKs cardiac repolarizing currents, in charge of finishing the cardiac action potential. Their assembly and traffic to the plasma membrane have been subject of discussion over the last years, with two opposite schools claiming an association early in the biogenesis versus a independent traffic to the plasma membrane, were both proteins would diffuse to assemble. We aimed in the present work to shed a light to this controversial topic. Kv channels have also been described in vascular smooth muscle, were they set the resting membrane potential and, therefore, control vascular tone. Kv7.1, Kv7.4 and Kv7.5 have been detected in different veins and arteries, were aberrations in their expression promote physiological alterations, but the specific role of each subunit remains unknown. In this scenario, the proposed objectives for the current PhD dissertation included the study of Kv7.1-KCNE1 complex, its assembly and traffic mechanisms. We hypothesized an unconventional secretion for the complex and suggest ER-PM junctions as the potential trafficking system. Therefore, we aim to characterize this structures and their implication in Kv7.1 membrane targeting. Finally, due to its implication in proliferation, their importance in cardiovascular system and their known role in some cancers, we studied the changes in the expression of Kv channels in endothelial-derived vascular tumors. We have been able to solve the traffic controversy of Kv7.1-KCNE1 complexes as they are not assembled early in their biogenesis. While KCNE1 is using the conventional secretion pathway, Kv7.1 takes an unconventional route that skips Golgi. Upon co-assembly, Kv7.1 redirects KCNE1 to this unconventional pathway. Moreover, we have proved that this non-conventional route are indeed ER-PM junctions, which also host the assembly of the complex. The molecular interactors of the channel during its ER-PM junction targeting have also been analysed during this PhD thesis, unravelling a complex and dynamic proteomic context. In addition, we have described for the first time the expression of Kv1.3, Kv1.5, Kv7.1 and Kv7.5 in endothelial cells of human veins and arteries. A remodelling of this composition is observed in different vascular cancers, related with the malignancy of the tumor in some of the cases.[cat] ls canals de potassi dependents (Kv) regulen processos fisiològics molt importants, com la proliferació, la migració o el volum cel·lular. La seva rellevància es posa de manifest amb les diferents patologies associades a alteracions en la expressió dels canals, incloent malalties cardiovasculars, cerebrals, autoimmunes o càncer. Es tracta de proteïnes transmembrana formades per l’associació de 4 subunitats α que s’uneixen per formar el por. La gran varietat de diversitat funcional és deguda a la capacitat de heterotetramerització dels canals, variants d’splicing, modificacions post-traduccionals o la associació a subunitats reguladores KCNE, entre d’altres. En cardiomiòcits, Kv7.1 s’associa a KCNE1 per generar les corrents IKs, encarregades de la repolarització del potencial cardíac. La seva associació i tràfic són tema de debat des de fa anys, amb dues escoles defensant idees oposades. La primera, que les dues proteïnes s’associen en les fases inicials de la biogènesi; la segona, que trafiquen independent cap a la membrana, on difondran per trobar-se. Els Kv també s’han detectat a musculatura vascular llisa, on mantenen el potencial de repòs i controlen així el to vascular. Kv7.1, Kv7.4 i Kv7.5 es troben en diferents venes i arteries, on una expressió aberrant provoca alteracions fisiològiques. Tot i així, el seu paper concret encara es desconeix. En la present tesi doctoral hem comprovat que Kv7.1 i KCNE1 utilitzen vies diferents per arribar a la membrana plasmàtica. KCNE1 viatja per la via convencional, mentre que Kv7.1 utilitza una ruta no convencional que escapa del Golgi. Quan co-expressats, Kv7.1 redirigeix KCNE1 cap aquesta via alternativa. Hem demostrat que aquesta via són les ER-PM junctions, que també són el compartiment on la seva associació té lloc. Els interactors moleculars del canal durant el seu tràfic cap a ER-PM junctions també s’ha estudiat durant aquest treball. A més a més, hem descrit per primer cop l’expressió de Kv1.3, Kv1.5, Kv7.1 i Kv7.5 en l’endoteli de venes i artèries humanes. Hem vist un remodelatge en aquesta expressió en diferents càncers vasculars, en alguns casos relacionat amb la malignitat del tumor

Biology of the cardiovascular Kv7.1 functional complex

Voltage gated K+ channels (Kv) are transmembrane proteins that allow the pass-thorugh of potassium ions, regulating the electrochemical gradient of the cell membrane. This way, they modulate several physiological processes, such as proliferation, migration or cell volume. Of particular interest in this dissertation is their role in excitable cells, were they control several key functions. The relevance of this ion channels is evidenced when mutations or alterations in the proper functioning of Kv channels causes severe pathologies, including cardiovascular or neuronal diseases, autoimmune affectations or cancer. Kv channels are tetramers of 4 α subunits with 6 transmembrane segments each one, that associate to form the pore and generate a functional channel. The wide functional diversity of currents is due to a vast number of modulations: heterotetramerization of α subunits, splicing variants, post-translational modifications or the association with regulatory subunits. The last ones include KCNE family, which co-assemble with the channel and modulate its electrophysiological, pharmacological or physiological properties. Kv7.1 associates with KCNE1 in cardiomyocytes to generate IKs cardiac repolarizing currents, in charge of finishing the cardiac action potential. Their assembly and traffic to the plasma membrane have been subject of discussion over the last years, with two opposite schools claiming an association early in the biogenesis versus a independent traffic to the plasma membrane, were both proteins would diffuse to assemble. We aimed in the present work to shed a light to this controversial topic. Kv channels have also been described in vascular smooth muscle, were they set the resting membrane potential and, therefore, control vascular tone. Kv7.1, Kv7.4 and Kv7.5 have been detected in different veins and arteries, were aberrations in their expression promote physiological alterations, but the specific role of each subunit remains unknown. In this scenario, the proposed objectives for the current PhD dissertation included the study of Kv7.1-KCNE1 complex, its assembly and traffic mechanisms. We hypothesized an unconventional secretion for the complex and suggest ER-PM junctions as the potential trafficking system. Therefore, we aim to characterize this structures and their implication in Kv7.1 membrane targeting. Finally, due to its implication in proliferation, their importance in cardiovascular system and their known role in some cancers, we studied the changes in the expression of Kv channels in endothelial-derived vascular tumors. We have been able to solve the traffic controversy of Kv7.1-KCNE1 complexes as they are not assembled early in their biogenesis. While KCNE1 is using the conventional secretion pathway, Kv7.1 takes an unconventional route that skips Golgi. Upon co-assembly, Kv7.1 redirects KCNE1 to this unconventional pathway. Moreover, we have proved that this non-conventional route are indeed ER-PM junctions, which also host the assembly of the complex. The molecular interactors of the channel during its ER-PM junction targeting have also been analysed during this PhD thesis, unravelling a complex and dynamic proteomic context. In addition, we have described for the first time the expression of Kv1.3, Kv1.5, Kv7.1 and Kv7.5 in endothelial cells of human veins and arteries. A remodelling of this composition is observed in different vascular cancers, related with the malignancy of the tumor in some of the cases.Els canals de potassi dependents (Kv) regulen processos fisiològics molt importants, com la proliferació, la migració o el volum cel·lular. La seva rellevància es posa de manifest amb les diferents patologies associades a alteracions en la expressió dels canals, incloent malalties cardiovasculars, cerebrals, autoimmunes o càncer. Es tracta de proteïnes transmembrana formades per l’associació de 4 subunitats α que s’uneixen per formar el por. La gran varietat de diversitat funcional és deguda a la capacitat de heterotetramerització dels canals, variants d’splicing, modificacions post-traduccionals o la associació a subunitats reguladores KCNE, entre d’altres. En cardiomiòcits, Kv7.1 s’associa a KCNE1 per generar les corrents IKs, encarregades de la repolarització del potencial cardíac. La seva associació i tràfic són tema de debat des de fa anys, amb dues escoles defensant idees oposades. La primera, que les dues proteïnes s’associen en les fases inicials de la biogènesi; la segona, que trafiquen independent cap a la membrana, on difondran per trobar-se. Els Kv també s’han detectat a musculatura vascular llisa, on mantenen el potencial de repòs i controlen així el to vascular. Kv7.1, Kv7.4 i Kv7.5 es troben en diferents venes i arteries, on una expressió aberrant provoca alteracions fisiològiques. Tot i així, el seu paper concret encara es desconeix. En la present tesi doctoral hem comprovat que Kv7.1 i KCNE1 utilitzen vies diferents per arribar a la membrana plasmàtica. KCNE1 viatja per la via convencional, mentre que Kv7.1 utilitza una ruta no convencional que escapa del Golgi. Quan co-expressats, Kv7.1 redirigeix KCNE1 cap aquesta via alternativa. Hem demostrat que aquesta via són les ER-PM junctions, que també són el compartiment on la seva associació té lloc. Els interactors moleculars del canal durant el seu tràfic cap a ER-PM junctions també s’ha estudiat durant aquest treball. A més a més, hem descrit per primer cop l’expressió de Kv1.3, Kv1.5, Kv7.1 i Kv7.5 en l’endoteli de venes i artèries humanes. Hem vist un remodelatge en aquesta expressió en diferents càncers vasculars, en alguns casos relacionat amb la malignitat del tumor

Biology of the cardiovascular Kv7.1 functional complex

Voltage gated K+ channels (Kv) are transmembrane proteins that allow the pass-thorugh of potassium ions, regulating the electrochemical gradient of the cell membrane. This way, they modulate several physiological processes, such as proliferation, migration or cell volume. Of particular interest in this dissertation is their role in excitable cells, were they control several key functions. The relevance of this ion channels is evidenced when mutations or alterations in the proper functioning of Kv channels causes severe pathologies, including cardiovascular or neuronal diseases, autoimmune affectations or cancer. Kv channels are tetramers of 4 α subunits with 6 transmembrane segments each one, that associate to form the pore and generate a functional channel. The wide functional diversity of currents is due to a vast number of modulations: heterotetramerization of α subunits, splicing variants, post-translational modifications or the association with regulatory subunits. The last ones include KCNE family, which co-assemble with the channel and modulate its electrophysiological, pharmacological or physiological properties. Kv7.1 associates with KCNE1 in cardiomyocytes to generate IKs cardiac repolarizing currents, in charge of finishing the cardiac action potential. Their assembly and traffic to the plasma membrane have been subject of discussion over the last years, with two opposite schools claiming an association early in the biogenesis versus a independent traffic to the plasma membrane, were both proteins would diffuse to assemble. We aimed in the present work to shed a light to this controversial topic. Kv channels have also been described in vascular smooth muscle, were they set the resting membrane potential and, therefore, control vascular tone. Kv7.1, Kv7.4 and Kv7.5 have been detected in different veins and arteries, were aberrations in their expression promote physiological alterations, but the specific role of each subunit remains unknown. In this scenario, the proposed objectives for the current PhD dissertation included the study of Kv7.1-KCNE1 complex, its assembly and traffic mechanisms. We hypothesized an unconventional secretion for the complex and suggest ER-PM junctions as the potential trafficking system. Therefore, we aim to characterize this structures and their implication in Kv7.1 membrane targeting. Finally, due to its implication in proliferation, their importance in cardiovascular system and their known role in some cancers, we studied the changes in the expression of Kv channels in endothelial-derived vascular tumors. We have been able to solve the traffic controversy of Kv7.1-KCNE1 complexes as they are not assembled early in their biogenesis. While KCNE1 is using the conventional secretion pathway, Kv7.1 takes an unconventional route that skips Golgi. Upon co-assembly, Kv7.1 redirects KCNE1 to this unconventional pathway. Moreover, we have proved that this non-conventional route are indeed ER-PM junctions, which also host the assembly of the complex. The molecular interactors of the channel during its ER-PM junction targeting have also been analysed during this PhD thesis, unravelling a complex and dynamic proteomic context. In addition, we have described for the first time the expression of Kv1.3, Kv1.5, Kv7.1 and Kv7.5 in endothelial cells of human veins and arteries. A remodelling of this composition is observed in different vascular cancers, related with the malignancy of the tumor in some of the cases.Els canals de potassi dependents (Kv) regulen processos fisiològics molt importants, com la proliferació, la migració o el volum cel·lular. La seva rellevància es posa de manifest amb les diferents patologies associades a alteracions en la expressió dels canals, incloent malalties cardiovasculars, cerebrals, autoimmunes o càncer. Es tracta de proteïnes transmembrana formades per l’associació de 4 subunitats α que s’uneixen per formar el por. La gran varietat de diversitat funcional és deguda a la capacitat de heterotetramerització dels canals, variants d’splicing, modificacions post-traduccionals o la associació a subunitats reguladores KCNE, entre d’altres. En cardiomiòcits, Kv7.1 s’associa a KCNE1 per generar les corrents IKs, encarregades de la repolarització del potencial cardíac. La seva associació i tràfic són tema de debat des de fa anys, amb dues escoles defensant idees oposades. La primera, que les dues proteïnes s’associen en les fases inicials de la biogènesi; la segona, que trafiquen independent cap a la membrana, on difondran per trobar-se. Els Kv també s’han detectat a musculatura vascular llisa, on mantenen el potencial de repòs i controlen així el to vascular. Kv7.1, Kv7.4 i Kv7.5 es troben en diferents venes i arteries, on una expressió aberrant provoca alteracions fisiològiques. Tot i així, el seu paper concret encara es desconeix. En la present tesi doctoral hem comprovat que Kv7.1 i KCNE1 utilitzen vies diferents per arribar a la membrana plasmàtica. KCNE1 viatja per la via convencional, mentre que Kv7.1 utilitza una ruta no convencional que escapa del Golgi. Quan co-expressats, Kv7.1 redirigeix KCNE1 cap aquesta via alternativa. Hem demostrat que aquesta via són les ER-PM junctions, que també són el compartiment on la seva associació té lloc. Els interactors moleculars del canal durant el seu tràfic cap a ER-PM junctions també s’ha estudiat durant aquest treball. A més a més, hem descrit per primer cop l’expressió de Kv1.3, Kv1.5, Kv7.1 i Kv7.5 en l’endoteli de venes i artèries humanes. Hem vist un remodelatge en aquesta expressió en diferents càncers vasculars, en alguns casos relacionat amb la malignitat del tumor

Remodeling of Kv7.1 and Kv7.5 Expression in Vascular Tumors

Voltage-dependent potassium (Kv) channels contribute to the excitability of nerves and muscles. In addition, Kv participates in several cell functions, including cell cycle progression and proliferation. Kv channel remodeling has been associated with neoplastic cell growth and cancer. Kv7 channels are expressed in blood vessels, and they participate in the maintenance of vascular tone and are implicated in myocyte proliferation. Although evidence links Kv7 remodeling to different types of cancer, its expression in vascular tumors has never been studied. Endothelium-derived vascular neoplasms range from indolent lesions to highly aggressive and metastasizing cancers. Here, we show that Kv7.1 and Kv7.5 are evenly distributed in tunicas as well as the endothelium of healthy veins and arteries. The layered structure of vessels is lost in vascular tumors. By studying eight vascular tumors with different origins and characteristics, we found that Kv7.1 and Kv7.5 expression was changed in vascular cancers. While both channels were generally downregulated, Kv7.5 expression was clearly correlated with neoplastic malignancy. The vascular tumors did not contract; therefore, the role of Kv7 channels is probably related to proliferation rather than controlling vascular tone. Our results identify vascular Kv7 channels as targets for cancer detection and anticancer therapies

The Potassium Channel Odyssey: Mechanisms of Traffic and Membrane Arrangement

Ion channels are transmembrane proteins that conduct specific ions across biological membranes. Ion channels are present at the onset of many cellular processes, and their malfunction triggers severe pathologies. Potassium channels (KChs) share a highly conserved signature that is necessary to conduct K+ through the pore region. To be functional, KChs require an exquisite regulation of their subcellular location and abundance. A wide repertoire of signatures facilitates the proper targeting of the channel, fine-tuning the balance that determines traffic and location. These signature motifs can be part of the secondary or tertiary structure of the protein and are spread throughout the entire sequence. Furthermore, the association of the pore-forming subunits with different ancillary proteins forms functional complexes. These partners can modulate traffic and activity by adding their own signatures as well as by exposing or masking the existing ones. Post-translational modifications (PTMs) add a further dimension to traffic regulation. Therefore, the fate of a KCh is not fully dependent on a gene sequence but on the balance of many other factors regulating traffic. In this review, we assemble recent evidence contributing to our understanding of the spatial expression of KChs in mammalian cells. We compile specific signatures, PTMs, and associations that govern the destination of a functional channel

Remodeling of Kv7.1 and Kv7.5 Expression in Vascular Tumors

Voltage-dependent potassium (Kv) channels contribute to the excitability of nerves and muscles. In addition, Kv participates in several cell functions, including cell cycle progression and proliferation. Kv channel remodeling has been associated with neoplastic cell growth and cancer. Kv7 channels are expressed in blood vessels, and they participate in the maintenance of vascular tone and are implicated in myocyte proliferation. Although evidence links Kv7 remodeling to different types of cancer, its expression in vascular tumors has never been studied. Endothelium-derived vascular neoplasms range from indolent lesions to highly aggressive and metastasizing cancers. Here, we show that Kv7.1 and Kv7.5 are evenly distributed in tunicas as well as the endothelium of healthy veins and arteries. The layered structure of vessels is lost in vascular tumors. By studying eight vascular tumors with different origins and characteristics, we found that Kv7.1 and Kv7.5 expression was changed in vascular cancers. While both channels were generally downregulated, Kv7.5 expression was clearly correlated with neoplastic malignancy. The vascular tumors did not contract; therefore, the role of Kv7 channels is probably related to proliferation rather than controlling vascular tone. Our results identify vascular Kv7 channels as targets for cancer detection and anticancer therapie