Key result
The phospho-deficient mutation S1076A attenuated the excitatory effect of the PKC activator PMA on BKCa channels, whereas the phospho-mimetic mutation S1076E increased it.
p-value: p=<0.05
Mutating the PKC phosphorylation site S1076 on human BK(Ca) channel alpha-subunits alters channel activity in response to PKC and PKG activation, providing mechanistic insights into pulmonary vascular tone regulation.
S1076 mutation alters PKC regulation of BKCa in vitro; leaves open its role in pulmonary vascular tone pending in vivo studies.
Large conductance, calcium- and voltage-activated potassium (BK(Ca)) channels are important modulators of pulmonary vascular smooth muscle membrane potential, and phosphorylation of BK(Ca) channels by protein kinases regulates pulmonary arterial smooth muscle function. However, little is known about the effect of phosphorylating specific channel subunits on BK(Ca) channel activity. The present study was done to determine the effect of mutating protein kinase C (PKC) phosphorylation site serine 1076 (S1076) on transfected human BK(Ca) channel alpha-subunits in human embryonic kidney (HEK-293) cells, a heterologous expression system devoid of endogenous BK(Ca) channels. Results showed that mutating S1076 altered the effect of PKC activation on BK(Ca) channels in HEK-293 cells. Specifically, the phospho-deficient mutation BK(Ca)-alpha(S1076A)/beta(1) attenuated the excitatory effect of the PKC activator phorbol myristate acetate (PMA) on BK(Ca) channels, whereas the phospho-mimetic mutation BK(Ca)-alpha(S1076E)/beta(1) increased the excitatory effect of PMA on BK(Ca) channels. In addition, the phospho-null mutation S1076A blocked the activating effect of cGMP-dependent protein kinase G (PKG) on BK(Ca) channels. Collectively, these results suggest that specific putative PKC phosphorylation site(s) on human BK(Ca) channel alpha-subunits influences BK(Ca) channel activity, which may subsequently alter pulmonary vascular smooth muscle function and tone.
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Zhu et al. (2009) studied this question. Mutation of PKC phosphorylation site S1076 (S1076A or S1076E) and PKC activation vs. Wild-type BKCa channels was evaluated on BKCa channel open probability (NPo) (p=<0.05). The phospho-deficient mutation S1076A attenuated the excitatory effect of the PKC activator PMA on BKCa channels, whereas the phospho-mimetic mutation S1076E increased it.
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