The non-b endocrine cells in pancreatic islets play an essential counterpart and regulatory role ... more The non-b endocrine cells in pancreatic islets play an essential counterpart and regulatory role to the insulin-producing b-cells in the regulation of blood-glucose homeostasis. While significant progress has been made towards the understanding of b-cell regeneration in adults, very little is known about the regeneration of the non-b endocrine cells such as glucagon-producing a-cells and somatostatin producing d-cells. Previous studies have noted the increase of a-cell composition in diabetes patients and in animal models. It is thus our hypothesis that non-b-cells such as a-cells and d-cells in adults can regenerate, and that the regeneration accelerates in diabetic conditions. To test this hypothesis, we examined islet cell composition in a streptozotocin (STZ)-induced diabetes mouse model in detail. Our data showed the number of a-cells in each islet increased following STZ-mediated b-cell destruction, peaked at Day 6, which was about 3 times that of normal islets. In addition, w...
Calcium Entry Channels in Non-Excitable Cells, 2017
The epithelial calcium (Ca2+) channels TRPV5 and TRPV6 are members of the transient receptor pote... more The epithelial calcium (Ca2+) channels TRPV5 and TRPV6 are members of the transient receptor potential (TRP) channel family TRPV (“V” for vanilloid) subgroup. TRPV5 and TRPV6 play major roles in the maintenance of blood Ca2+ levels in higher organisms. Both channels exhibit similarities in many ways, as they share a high level (75%) of amino acid identity, comparable functional properties, and similar mechanisms of regulation. Also, they were discovered using similar cloning strategies [1,2]. Yet, their physiological contributions toward maintaining a systemic calcium balance are distinct. In addition, the following three key features distinguish TRPV5 and TRPV6 from other members of the TRP superfamily of cation channels: (1) high selectivity for Ca2+ over other cations, (2) apical membrane localization in Ca2+-transporting epithelial tissues, and (3) responsiveness to 1,25-dihydroxyvitamin D3 (1,25[OH]2D3) [3,4]. These features make TRPV5 and TRPV6 ideally suited to facilitate intestinal absorption and renal reabsorption of Ca2+, serving as apical Ca2+ entry channels in transepithelial Ca2+ transport [5,6]. A major difference between the properties of TRPV5 and TRPV6 lies in their tissue distribution: TRPV5 is predominantly expressed in the distal convoluted tubules (DCT) and connecting tubules (CNT) of the kidney, with limited expression in extrarenal tissues [1,7]. In contrast, TRPV6 exhibits a broader expression pattern, showing prominent expression in the intestine with additional expression in the kidney [8–10], placenta, epididymis, exocrine tissues (i.e., pancreas, prostate, salivary gland, sweat gland), and a few other tissues [11–13]. Thus, while TRPV5 plays a key role in determining the level of urinary Ca2+ excretion, the physiological roles of TRPV6 are not limited to intestinal Ca2+ absorption. Much progress has recently been made in understanding the roles of TRPV5 and TRPV6 channels in the kidney [14], intestine [15], placenta [16], and epididymis [17]. However, their roles in other organs have as yet not been fully investigated.In this chapter, we review the current status of our knowledge of the physiological and pathological roles of TRPV5 and TRPV6 and discuss a variety of techniques that have led to a deeper understanding of these channels. We review the identification strategies of TRPV5 and TRPV6 in searches for Ca2+ absorption channels, as well as specific techniques used to reveal their key features. These include radiotracer Ca2+ uptake and electrophysiology procedures, structure-function studies, methods to identify regulatory interacting partners, genetically engineered animals, strategies to study the role of TRPV6 in cancers, procedures for the development of small-molecule modulators of TRPV6 and TRPV5, the evaluation of variations/mutations in humans, and 3D structural determination. For additional information about TRPV5 and TRPV6, we would like to refer the interested reader to other comprehensive review articles [3–6,18].
Dr. Peng received his Ph.D. degree from Shanghai Institute of Cell Biology of the Chinese Academy... more Dr. Peng received his Ph.D. degree from Shanghai Institute of Cell Biology of the Chinese Academy of Sciences. Dr. Peng had his postdoctoral training at Brigham & Women’s Hospital and Harvard Medical School during 1997 to 2000 (Mentored by Drs. Matthias Hediger and Edward Brown). He became an Instructor in Medicine at Harvard Medical School in 2000. Dr. Peng Joined the University of Alabama at Birmingham (UAB) as an Assistant Professor in 2003. He is currently an Associate Professor of Medicine at UAB.
The human epithelial channels, CaT1 and CaT2, were expressed in oocytes, and their single-channel... more The human epithelial channels, CaT1 and CaT2, were expressed in oocytes, and their single-channel characteristics were compared. In the presence of Na+ and K+ as charge carriers in the pipette solutions, channel activities were observed only when the the extracellular sides of the patches were exposed to nominally Ca2+- and Mg2+-free solutions. In patches of both CaT1- and CaT2-expressing oocytes, multiple channel openings were observed, but the current levels were higher in CaT2-expressing oocytes, particularly at more negative voltages. With K+ as a charge carrier in patches of CaT1-expressing oocytes, the channel activity was low at -10 to -60 mV, but increased dramatically at more negative potentials. This voltage dependence was observed in the presence of both Na+ and K+. The channel activity with Na+, however, was higher at all potentials. Differences between the voltage dependencies for the two cations were also observed in CaT2-expressing oocytes, but the channel activities were higher than those in CaT1-expressing oocytes, particularly in the presence of Na+. We also found that low concentrations of extracellular Mg2+ (5-50 microm) elicited a strong inhibitory action on the CaT channels. Activation of the CaT1 and CaT2 channels by hyperpolarization and other factors may promote increased Ca2+ entry that participates in stimulation of intestinal absorption and renal reabsorption and/or other Ca2+ transport mechanisms in epithelial cells.
Calcium-selective channel TRPV6 (Transient Receptor Potential channel family, Vanilloid subfamily... more Calcium-selective channel TRPV6 (Transient Receptor Potential channel family, Vanilloid subfamily member 6) belongs to the TRP family of cation channels and plays critical roles in transcellular calcium (Ca2+) transport, reuptake of Ca2+ into cells, and maintaining a local low Ca2+ environment for certain biological processes. Recent crystal and cryo-electron microscopy-based structures of TRPV6 have revealed mechanistic insights on how the protein achieves Ca2+ selectivity, permeation, and inactivation by calmodulin. The TRPV6 protein is expressed in a range of epithelial tissues such as the intestine, kidney, placenta, epididymis, and exocrine glands such as the pancreas, prostate and salivary, sweat, and mammary glands. The TRPV6 gene is a direct transcriptional target of the active form of vitamin D and is efficiently regulated to meet the body's need for Ca2+ demand. In addition, TRPV6 is also regulated by the level of dietary Ca2+ and under physiological conditions such as pregnancy and lactation. Genetic models of loss of function in TRPV6 display hypercalciuria, decreased bone marrow density, deficient weight gain, reduced fertility, and in some cases alopecia.The models also reveal that the channel plays an indispensable role in maintaining maternal-fetal Ca2+ transport and low Ca2+ environment in the epididymal lumen that is critical for male fertility. Most recently, loss of function mutations in TRPV6 gene is linked to transient neonatal hyperparathyroidism and early onset chronic pancreatitis. TRPV6 is overexpressed in a wide range of human malignancies and its upregulation is strongly correlated to tumor aggressiveness, metastasis, and poor survival in selected cancers. This review summarizes the current state of knowledge on the expression, structure, biophysical properties, function, polymorphisms, and regulation of TRPV6. The aberrant expression, polymorphisms, and dysfunction of this protein linked to human diseases are also discussed.
L'invention porte sur des sequences d'acide nucleique et d'acide amine correspondant ... more L'invention porte sur des sequences d'acide nucleique et d'acide amine correspondant a une proteine de transport du calcium qui regule le deplacement du calcium dans les membranes cellulaires.
The non-b endocrine cells in pancreatic islets play an essential counterpart and regulatory role ... more The non-b endocrine cells in pancreatic islets play an essential counterpart and regulatory role to the insulin-producing b-cells in the regulation of blood-glucose homeostasis. While significant progress has been made towards the understanding of b-cell regeneration in adults, very little is known about the regeneration of the non-b endocrine cells such as glucagon-producing a-cells and somatostatin producing d-cells. Previous studies have noted the increase of a-cell composition in diabetes patients and in animal models. It is thus our hypothesis that non-b-cells such as a-cells and d-cells in adults can regenerate, and that the regeneration accelerates in diabetic conditions. To test this hypothesis, we examined islet cell composition in a streptozotocin (STZ)-induced diabetes mouse model in detail. Our data showed the number of a-cells in each islet increased following STZ-mediated b-cell destruction, peaked at Day 6, which was about 3 times that of normal islets. In addition, w...
Calcium Entry Channels in Non-Excitable Cells, 2017
The epithelial calcium (Ca2+) channels TRPV5 and TRPV6 are members of the transient receptor pote... more The epithelial calcium (Ca2+) channels TRPV5 and TRPV6 are members of the transient receptor potential (TRP) channel family TRPV (“V” for vanilloid) subgroup. TRPV5 and TRPV6 play major roles in the maintenance of blood Ca2+ levels in higher organisms. Both channels exhibit similarities in many ways, as they share a high level (75%) of amino acid identity, comparable functional properties, and similar mechanisms of regulation. Also, they were discovered using similar cloning strategies [1,2]. Yet, their physiological contributions toward maintaining a systemic calcium balance are distinct. In addition, the following three key features distinguish TRPV5 and TRPV6 from other members of the TRP superfamily of cation channels: (1) high selectivity for Ca2+ over other cations, (2) apical membrane localization in Ca2+-transporting epithelial tissues, and (3) responsiveness to 1,25-dihydroxyvitamin D3 (1,25[OH]2D3) [3,4]. These features make TRPV5 and TRPV6 ideally suited to facilitate intestinal absorption and renal reabsorption of Ca2+, serving as apical Ca2+ entry channels in transepithelial Ca2+ transport [5,6]. A major difference between the properties of TRPV5 and TRPV6 lies in their tissue distribution: TRPV5 is predominantly expressed in the distal convoluted tubules (DCT) and connecting tubules (CNT) of the kidney, with limited expression in extrarenal tissues [1,7]. In contrast, TRPV6 exhibits a broader expression pattern, showing prominent expression in the intestine with additional expression in the kidney [8–10], placenta, epididymis, exocrine tissues (i.e., pancreas, prostate, salivary gland, sweat gland), and a few other tissues [11–13]. Thus, while TRPV5 plays a key role in determining the level of urinary Ca2+ excretion, the physiological roles of TRPV6 are not limited to intestinal Ca2+ absorption. Much progress has recently been made in understanding the roles of TRPV5 and TRPV6 channels in the kidney [14], intestine [15], placenta [16], and epididymis [17]. However, their roles in other organs have as yet not been fully investigated.In this chapter, we review the current status of our knowledge of the physiological and pathological roles of TRPV5 and TRPV6 and discuss a variety of techniques that have led to a deeper understanding of these channels. We review the identification strategies of TRPV5 and TRPV6 in searches for Ca2+ absorption channels, as well as specific techniques used to reveal their key features. These include radiotracer Ca2+ uptake and electrophysiology procedures, structure-function studies, methods to identify regulatory interacting partners, genetically engineered animals, strategies to study the role of TRPV6 in cancers, procedures for the development of small-molecule modulators of TRPV6 and TRPV5, the evaluation of variations/mutations in humans, and 3D structural determination. For additional information about TRPV5 and TRPV6, we would like to refer the interested reader to other comprehensive review articles [3–6,18].
Dr. Peng received his Ph.D. degree from Shanghai Institute of Cell Biology of the Chinese Academy... more Dr. Peng received his Ph.D. degree from Shanghai Institute of Cell Biology of the Chinese Academy of Sciences. Dr. Peng had his postdoctoral training at Brigham & Women’s Hospital and Harvard Medical School during 1997 to 2000 (Mentored by Drs. Matthias Hediger and Edward Brown). He became an Instructor in Medicine at Harvard Medical School in 2000. Dr. Peng Joined the University of Alabama at Birmingham (UAB) as an Assistant Professor in 2003. He is currently an Associate Professor of Medicine at UAB.
The human epithelial channels, CaT1 and CaT2, were expressed in oocytes, and their single-channel... more The human epithelial channels, CaT1 and CaT2, were expressed in oocytes, and their single-channel characteristics were compared. In the presence of Na+ and K+ as charge carriers in the pipette solutions, channel activities were observed only when the the extracellular sides of the patches were exposed to nominally Ca2+- and Mg2+-free solutions. In patches of both CaT1- and CaT2-expressing oocytes, multiple channel openings were observed, but the current levels were higher in CaT2-expressing oocytes, particularly at more negative voltages. With K+ as a charge carrier in patches of CaT1-expressing oocytes, the channel activity was low at -10 to -60 mV, but increased dramatically at more negative potentials. This voltage dependence was observed in the presence of both Na+ and K+. The channel activity with Na+, however, was higher at all potentials. Differences between the voltage dependencies for the two cations were also observed in CaT2-expressing oocytes, but the channel activities were higher than those in CaT1-expressing oocytes, particularly in the presence of Na+. We also found that low concentrations of extracellular Mg2+ (5-50 microm) elicited a strong inhibitory action on the CaT channels. Activation of the CaT1 and CaT2 channels by hyperpolarization and other factors may promote increased Ca2+ entry that participates in stimulation of intestinal absorption and renal reabsorption and/or other Ca2+ transport mechanisms in epithelial cells.
Calcium-selective channel TRPV6 (Transient Receptor Potential channel family, Vanilloid subfamily... more Calcium-selective channel TRPV6 (Transient Receptor Potential channel family, Vanilloid subfamily member 6) belongs to the TRP family of cation channels and plays critical roles in transcellular calcium (Ca2+) transport, reuptake of Ca2+ into cells, and maintaining a local low Ca2+ environment for certain biological processes. Recent crystal and cryo-electron microscopy-based structures of TRPV6 have revealed mechanistic insights on how the protein achieves Ca2+ selectivity, permeation, and inactivation by calmodulin. The TRPV6 protein is expressed in a range of epithelial tissues such as the intestine, kidney, placenta, epididymis, and exocrine glands such as the pancreas, prostate and salivary, sweat, and mammary glands. The TRPV6 gene is a direct transcriptional target of the active form of vitamin D and is efficiently regulated to meet the body's need for Ca2+ demand. In addition, TRPV6 is also regulated by the level of dietary Ca2+ and under physiological conditions such as pregnancy and lactation. Genetic models of loss of function in TRPV6 display hypercalciuria, decreased bone marrow density, deficient weight gain, reduced fertility, and in some cases alopecia.The models also reveal that the channel plays an indispensable role in maintaining maternal-fetal Ca2+ transport and low Ca2+ environment in the epididymal lumen that is critical for male fertility. Most recently, loss of function mutations in TRPV6 gene is linked to transient neonatal hyperparathyroidism and early onset chronic pancreatitis. TRPV6 is overexpressed in a wide range of human malignancies and its upregulation is strongly correlated to tumor aggressiveness, metastasis, and poor survival in selected cancers. This review summarizes the current state of knowledge on the expression, structure, biophysical properties, function, polymorphisms, and regulation of TRPV6. The aberrant expression, polymorphisms, and dysfunction of this protein linked to human diseases are also discussed.
L'invention porte sur des sequences d'acide nucleique et d'acide amine correspondant ... more L'invention porte sur des sequences d'acide nucleique et d'acide amine correspondant a une proteine de transport du calcium qui regule le deplacement du calcium dans les membranes cellulaires.
Uploads
Papers