A major interspecies difference in the ionic selectivity of megakaryocyte Ca2+-activated channels sensitive to the TMEM16F inhibitor CaCCinh-A01

Autor: Martyn P. Mahaut-Smith, Kirk A. Taylor
Rok vydání: 2019
Předmět:
PHOSPHATIDYLSERINE EXPOSURE
0301 basic medicine
Phospholipid scramblase
030204 cardiovascular system & hematology
ACTIVATION
megakaryocyte
phospholipid scrambling
Mice
0302 clinical medicine
Phospholipid scrambling
Megakaryocyte
Scott syndrome
Platelet
Phospholipid Transfer Proteins
platelet
Chemistry
Hematology
General Medicine
Membrane
medicine.anatomical_structure
Chloride channel
CL-CHANNEL
ANOCTAMIN 6
Life Sciences & Biomedicine
Megakaryocytes
EXPRESSION
Anoctamins
HUMAN PLATELETS
03 medical and health sciences
medicine
Animals
Humans
CELL
Ion channel
Science & Technology
CONDUCTANCE
CHLORIDE CHANNELS
TMEM16F
1103 Clinical Sciences
Biological Transport
Cell Biology
medicine.disease
Rats
030104 developmental biology
Cardiovascular System & Hematology
Biophysics
Calcium
Plenary Paper and Short Communication
MEMBRANE
Zdroj: Platelets
ISSN: 1369-1635
0953-7104
DOI: 10.1080/09537104.2019.1595560
Popis: TMEM16F is a surface membrane protein critical for platelet procoagulant activity, which exhibits both phospholipid scramblase and ion channel activities following sustained elevation of cytosolic Ca2+. The extent to which the ionic permeability of TMEM16F is important for platelet scramblase responses remains controversial. To date, only one study has reported the electrophysiological properties of TMEM16F in cells of platelet/megakaryocyte lineage, which observed cation-selectivity within excised patch recordings from murine marrow-derived megakaryocytes. This contrasts with reports using whole-cell recordings that describe this channel as displaying either selectivity for anions or being relatively non-selective amongst the major physiological monovalent ions. We have studied TMEM16F expression and channel activity in primary rat and mouse megakaryocytes and the human erythroleukemic (HEL) cell line that exhibits megakaryocytic surface markers. Immunocytochemical analysis was consistent with surface TMEM16F expression in cells from all three species. Whole-cell recordings in the absence of K+-selective currents revealed an outwardly rectifying conductance activated by a high intracellular Ca2+ concentration in all three species. These currents appeared after 5–6 minutes and were blocked by CaCCinh-A01, properties typical of TMEM16F. Ion substitution experiments showed that the underlying conductance was predominantly Cl–-permeable in rat megakaryocytes and HEL cells, yet non-selective between monovalent anions and cations in mouse megakaryocytes. In conclusion, the present study further highlights the difference in ionic selectivity of TMEM16F in platelet lineage cells of the mouse compared to other mammalian species. This provides additional support for the ionic “leak” hypothesis that the scramblase activity of TMEM16F does not rely upon its ability to conduct ions of a specific type.
Databáze: OpenAIRE
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