Abstract:
:We evaluated whether phospholemman (PLM) regulates L-type Ca(2+) current (ICa) in mouse ventricular myocytes. Expression of α1-subunit of L-type Ca(2+) channels between wild-type (WT) and PLM knockout (KO) hearts was similar. Compared to WT myocytes, peak ICa (at -10 mV) from KO myocytes was ~41% larger, the inactivation time constant (τ(inact)) of ICa was ~39% longer, but deactivation time constant (τ(deact)) was similar. In the presence of isoproterenol (1 μM), peak ICa was ~48% larger and τ(inact) was ~144% higher in KO myocytes. With Ba(2+) as the permeant ion, PLM enhanced voltage-dependent inactivation but had no effect on τ(deact). To dissect the molecular determinants by which PLM regulated ICa, we expressed PLM mutants by adenovirus-mediated gene transfer in cultured KO myocytes. After 24h in culture, KO myocytes expressing green fluorescent protein (GFP) had significantly larger peak ICa and longer τ(inact) than KO myocytes expressing WT PLM; thereby independently confirming the observations in freshly isolated myocytes. Compared to KO myocytes expressing GFP, KO myocytes expressing the cytoplasmic domain truncation mutant (TM43), the non-phosphorylatable S68A mutant, the phosphomimetic S68E mutant, and the signature PFXYD to alanine (ALL5) mutant all resulted in lower peak ICa. Expressing PLM mutants did not alter expression of α1-subunit of L-type Ca(2+) channels in cultured KO myocytes. Our results suggested that both the extracellular PFXYD motif and the transmembrane domain of PLM but not the cytoplasmic tail were necessary for regulation of peak ICa amplitude. We conclude that PLM limits Ca(2+) influx in cardiac myocytes by reducing maximal ICa and accelerating voltage-dependent inactivation.
journal_name
J Mol Cell Cardioljournal_title
Journal of molecular and cellular cardiologyauthors
Zhang XQ,Wang J,Song J,Rabinowitz J,Chen X,Houser SR,Peterson BZ,Tucker AL,Feldman AM,Cheung JYdoi
10.1016/j.yjmcc.2015.04.017subject
Has Abstractpub_date
2015-07-01 00:00:00pages
104-11eissn
0022-2828issn
1095-8584pii
S0022-2828(15)00133-9journal_volume
84pub_type
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