A mechanogated nonselective cation channel in proximal tubule that is ATP sensitive

Abstract

Ion channels that are gated in response to membrane deformation or “stretch” are empirically designated stretch-activated channels. Here we describe a stretch-activated nonselective cation channel in the basolateral membrane (BLM) of the proximal tubule (PT) that is nucleotide sensitive. Single channels were studied in cell-intact and cell-free patches from the BLM of PT cells that maintain their epithelial polarity. The limiting inward Cs+ conductance is ∼28 pS, and channel activity persists after excision into a Ca2+- and ATP-free bath. The stretch-dose response is sigmoidal, with half-maximal activation of about −19 mmHg at −40 mV, and the channel is activated by depolarization. The inward conductance sequence is: NH[Formula: see text] ∼ Cs+ ∼ Rb+> K+ ∼ Na+ ∼ Li+ > Ca2+ ∼ Ba2+> N-methyl-d-glucamine ∼ tetraethylammonium. The venom of the common Chilean tarantula, Grammostola spatulata, completely blocks channel activity in cell-attached patches. Hypotonic swelling reversibly activates the channel. Intracellular ATP concentration ([ATP]i) reversibly blocks the channel (inhibitory constant ∼0.48 mM), suggesting that channel function is coupled to the metabolic state of the cell. We conclude that this channel may function as a Ca2+ entry pathway and/or be involved in regulation of cell volume. We speculate this channel may be important when [ATP]i is depleted, as occurs during periods of increased transepithelial transport or with ischemic injury.

Intracellular nucleotides and polyamines inhibit the Ca 2+ -activated cation channel TRPM4b

“…Block by ATP is Mg 2+ independent. This block is similar to that described in vomeronasal sensory neurons [10], a mechanogated cation channel in kidney [6], in brown adipocytes [4] and in cardiomyocytes [3]. The mechanism of this block is unclear.…”

From cardiac cation channels to the molecular dissection of the transient receptor potential channel TRPM4

“…Similar currents have been described in many tissues, e.g., cardiomyocytes [11][12][13] in neurons from entorhinal cortex [24,25], dorsal root and vomeronasal neurons [21], neuroblastoma cells and astrocytes [9,46], vascular and myometrial smooth muscle [10,29], endocrine pancreas cells [48], in red blood cells [42], exocrine cells from the pancreas [52], brown adipocytes [17,45], kidney epithelial cells [16], cochlear hair cells [56,57], and vascular endothelial cells [7,51]. From a functional point of view, it is widely believed that TRPM4 causes membrane depolarization and thus limits the driving force for Ca 2+ entry.…”

Cell biology and physiology of the uroepithelium

“…The function of ENaC in this response is unclear, but it may act to depolarize the apical membrane in response to stretch, thus driving Ca 2ϩ into the cell. There are many examples of NSCCs that are voltage sensitive (95,103,187), and activation of ENaC could drive the opening of the NSCC. Alternatively, increased Na ϩ absorption through ENaC may modulate cross talk between ion channels at the apical and basolateral domains of the umbrella cells, changing the driving force for apical Ca 2ϩ entry.…”