VOLTAGE-DEPENDENT POTENTIATION OF L-TYPE CA2+ CHANNELS IN SKELETAL-MUSCLE CELLS REQUIRES ANCHORED CAMP-DEPENDENT PROTEIN-KINASE
VOLTAGE-DEPENDENT POTENTIATION OF L-TYPE CA2+ CHANNELS IN SKELETAL-MUSCLE CELLS REQUIRES ANCHORED CAMP-DEPENDENT PROTEIN-KINASE
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DOI：
10.1073/pnas.91.24.11492
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发表时间：
1994-11-22
影响因子：
11.1
通讯作者：
CATTERALL, WA
中科院分区：
文献类型：
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作者：
JOHNSON, BD;SCHEUER, T;CATTERALL, WA
骨骼肌L-型钙通道对短暂去极化的反应，通道激活的电压依赖性向更负的膜电位强烈转移，通道失活减慢。通道活性增强导致的Ca 2+进入增加可能会增加对强直刺激的收缩力。这种电压依赖性Ca 2+通道增强需要cAMP依赖性蛋白激酶（PKA）以一定的速率磷酸化，这表明激酶和通道可以通过激酶锚定保持紧密接近。从PKA锚定蛋白（AKAP）的保守激酶结合结构域衍生的肽防止内源性PKA的增强作用，其效果与通过特异性肽抑制剂或通过从细胞内溶液中省略ATP来抑制PKA一样有效。相比之下，AKAP肽的脯氨酸取代的突变体没有影响。在PKA的2 μ M外源性催化亚基的存在下的增强不受影响，表明激酶锚定被AKAP肽特异性阻断。没有观察到这些药物对增强前基础Ca 2+通道活性的水平或电压依赖性的影响，表明骨骼肌Ca 2+通道和PKA之间的紧密物理接近对于Ca 2+通道活性的电压依赖性增强是至关重要的，但对于基础活性不是。
Skeletal muscle L-type Ca2+ channels respond to trains of brief depolarizations with a strong shift of the voltage dependence of channel activation toward more negative membrane potentials and slowing of channel deactivation. Increased Ca2+ entry resulting from this potentiation of channel activity may increase contractile force in response to tetanic stimuli. This voltage-dependent Ca2+ channel potentiation requires phosphorylation by cAMP-dependent protein kinase (PKA) at a rate that suggests that kinase and channel may be maintained in close proximity through kinase anchoring. A peptide derived from the conserved kinase-binding domain of a PKA-anchoring protein (AKAP) prevents potentiation by endogenous PKA as effectively as inhibition of PKA by a specific peptide inhibitor or by omission of ATP from the intracellular solution. In contrast, a proline-substituted mutant of AKAP peptide has no effect. Potentiation in the presence of 2 mu M exogenous catalytic subunit of PKA is unaffected, indicating that kinase anchoring is specifically blocked by the AKAP peptide. No effects of these agents were observed on the level or voltage dependence of basal Ca2+ channel activity before potentiation, suggesting that close physical proximity between the skeletal muscle Ca2+ channel and PKA is critical for voltage-dependent potentiation of Ca2+ channel activity but not for basal activity.