The Role of Acid-Sensing Ion Channel 3 in Blood Volume Control and pH Homeostasis

• Main Authors: Cheng-Han Lee, 李政翰
• Other Authors: Synthia H. Sun
• Format: Others
• Language: en_US
• Published: 2011
• Online Access: http://ndltd.ncl.edu.tw/handle/74294374937438802265

博士 === 國立陽明大學 === 神經科學研究所 === 99 === Homeostasis of blood volume and systemic body pH is important for animal survival. Neural regulation of blood volume is largely through sensation of volume change by the mechano-sensitive volume receptors, which are located in primary sensory nerve terminals and carotid body. Volume receptors detect a stretching force induced by an increase in the intravascular volume, and then trigger a reflex mechanism to restore blood volume homeostasis. Regulation of systemic body pH within a narrow range of 7.35~7.45 requires sensitive acid‐sensing molecules to monitor changes in extracellular protons. In spite of years of research, the molecular mechanisms in volume receptors and acid sensors regulate blood volume and body pH remain largely unknown. Recent studies suggested that acid-sensing ion channel 3 (ASIC3) was involved in the mechano-transduction in the skin and colon afferent neurons. Moreover, ASIC3 is the most sensitive proton sensor in body and is mainly expressed in peripheral tissues including dorsal root ganglia. We hypothesized that ASIC3 served as the mechano-sensing volume receptors and also an important proton sensor to maintain both blood volume and body pH. To address this important issue, we examined and compared the physiological and neuronal responses, and acid‐base status in blood and urine between ASIC3 wild type and knockout (KO) mice under blood volume expansion (BVE). Indeed, the BVE-induced urine output was less in Asic3 knockout mice and amiloride-pretreatment wild type mice. Besides, the stretch-activated channels blocker, GdCl3, could further inhibit the BVE-induced urine excretion in ASIC3 KO mice. BVE significantly induced phosphorylated ERK (pERK) signal in nodose ganglia, and several dorsal root ganglia (DRG) in mice. BVE-induced pERK response was decreased by GdCl3 treatment. In nodose ganglia, the BVE-induced pERK response was much reduced in KO than in wild type mice with GdCl3-pretreatment. BVE induced an increase in plasma ANP which highly correlated pERK response in nodose. In comparison with wild type mice, both KOs and GdCl3-treated wild type mice had fewer BVE-induced c-Fos positive cells in NTS. Analysis of acid-base status showed that KO mice developed hyperkalemia, hyperchloremia metabolic acidosis with higher water excretion, hypotension, hypovolemia and bone loss. Taken together, we concluded that ASIC3 was involved in blood volume regulation through a GdCl3-independent manner and in maintenance of body acid-base homeostasis.