Department of Physiology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile.
Brain Res. 2010 Apr 6;1323:74-83. doi: 10.1016/j.brainres.2010.01.091. Epub 2010 Feb 11.
The carotid body is the main peripheral arterial chemoreceptor and it is essential to initiate the cardiovascular and respiratory compensatory reflex responses to a decrease in the arterial oxygen. The carotid body chemoreceptor (type-I) cells respond to hypoxia with membrane depolarization, voltage-gated Ca(2+) entry and secretion of transmitters. A key step in this response is the inhibition of a TASK-like background K(+) current. It has been reported that TASK-K(+) channels can be modulated by G-protein coupled receptors, such as the muscarinic acetylcholine receptor (mAChRs). Since there is a proposed role for ACh as an autocrine/paracrine modulator of the carotid body function, we have investigated the possible regulation of the background K(+) current by mAChRs. In identified type-I cells, methacholine (100microM) or muscarine (50microM) increased intracellular Ca(2+) levels. In cell-attached patch recordings, TASK-K(+) background channel activity was reduced by approximately 50% during mAChR activation and by the diacylglycerol analogue oleoylacetylglycerol (OAG, 20microM). The co-application of both metacholine and OAG do not further inhibit K(+) channel activity. In addition, two chemically different inhibitors of protein kinase C activity, calphostin C (100nM) and chelerythrine (50microM) are both able to suppress the muscarinic inhibition of the TASK-like K(+) channel and to increase channel activity in the absence of mAChR agonists. Our results suggest a muscarinic regulation of the TASK-like K(+) current in rat carotid body type-I cells through a PLC/PKC-dependent pathway. Additionally, our findings are consistent with an autocrine/paracrine role for cholinergic autoreceptors present within the carotid body.
颈动脉体是主要的外周动脉化学感受器，对于启动心血管和呼吸代偿反射以应对动脉血氧降低至关重要。颈动脉体化学感受器（I 型）细胞在缺氧时通过膜去极化、电压门控 Ca(2+) 内流和递质分泌来响应。这个反应的关键步骤是抑制 TASK 样背景 K(+) 电流。据报道，TASK-K(+) 通道可被 G 蛋白偶联受体（如毒蕈碱乙酰胆碱受体（mAChRs））调节。由于 ACh 被认为是颈动脉体功能的自分泌/旁分泌调节剂，因此我们研究了 mAChRs 对背景 K(+) 电流的可能调节作用。在鉴定的 I 型细胞中，乙酰甲胆碱（100μM）或毒蕈碱（50μM）增加细胞内 Ca(2+) 水平。在细胞贴附式膜片钳记录中，mAChR 激活时 TASK-K(+) 背景通道活性降低约 50%，二酰基甘油类似物油酰基乙酰甘油（OAG，20μM）也是如此。同时应用乙酰甲胆碱和 OAG 不会进一步抑制 K(+) 通道活性。此外，两种化学性质不同的蛋白激酶 C 活性抑制剂，钙调蛋白（100nM）和Chelerythrine（50μM）都能够抑制毒蕈碱对 TASK 样 K(+) 通道的抑制作用，并在没有 mAChR 激动剂的情况下增加通道活性。我们的结果表明，大鼠颈动脉体 I 型细胞中的 TASK 样 K(+) 电流受到 PLC/PKC 依赖性途径的调节。此外，我们的发现与颈动脉体中存在的胆碱能自身受体的自分泌/旁分泌作用一致。
