Rianopátiák kórélettana és gyógyszertana(FK 144576) Funder: NRDIO
A T4709M mutáns rianodin receptor funkcionális és farmakológiai jellemzése egyedi
csatorna szinten(ÚNKP-22-4-I-DE-28) Funder: MIT
Subjects:
Biophysics
Physiology (including cytology)
Physiological biophysics
Physiological muscle contraction requires an intact ligand gating mechanism of the
ryanodine receptor 1 (RyR1), the Ca 2+ -release channel of the sarcoplasmic reticulum.
Some mutations impair the gating and thus cause muscle disease. The RyR1 mutation
T4706M is linked to a myopathy characterized by muscle weakness. Although, low expression
of the T4706M RyR1 protein can explain in part the symptoms, little is known about
the function RyR1 channels with this mutation. In order to learn whether this mutation
alters channel function in a manner that can account for the observed symptoms, we
examined RyR1 channels isolated from mice homozygous for the T4709M (TM) mutation
at the single channel level. Ligands, including Ca 2+ , ATP, Mg 2+ and the RyR inhibitor
dantrolene were tested. The full conductance of the TM channel was the same as that
of wild type (wt) channels and a population of partial open (subconductive) states
were not observed. However, two unique sub-populations of TM RyRs were identified.
One half of the TM channels exhibited high open probability at low (100 nM) and high
(50 μM) cytoplasmic [Ca 2+ ], resulting in Ca 2+ -insensitive, constitutively high
P o channels. The rest of the TM channels exhibited significantly lower activity within
the physiologically relevant range of cytoplasmic [Ca 2+ ], compared to wt. TM channels
retained normal Mg 2+ block, modulation by ATP, and inhibition by dantrolene. Together,
these results suggest that the TM mutation results in a combination of primary and
secondary RyR1 dysfunctions that contribute to disease pathogenesis.
