Dual Regulation of Voltage-Sensitive Ion Channels by PIP2

Abstract

Over the past 16 years, there has been an impressive number of ion channels shown to be sensitive to the major phosphoinositide in the plasma membrane, phosphatidylinositol 4,5-bisphosphate (PIP2). Among them are voltage-gated channels, which are crucial for both neuronal and cardiac excitability. Voltage-gated calcium (Cav) channels were shown to be regulated bidirectionally by PIP2. On one hand, PIP2 stabilized their activity by reducing current rundown but on the other hand it produced a voltage-dependent inhibition by shifting the activation curve to more positive voltages. For voltage-gated potassium (Kv) channels PIP2 was first shown to prevent N-type inactivation regardless of whether the fast inactivation gate was part of the pore-forming α subunit or of an accessory β subunit. Careful examination of the effects of PIP2 on the activation mechanism of Kv1.2 has shown a similar bidirectional regulation as in the Cav channels. The two effects could be distinguished kinetically, in terms of their sensitivities to PIP2 and by distinct molecular determinants. The rightward shift of the Kv1.2 voltage dependence implicated basic residues in the S4–S5 linker and was consistent with stabilization of the inactive state of the voltage sensor. A third type of a voltage-gated ion channel modulated by PIP2 is the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel. PIP2 has been shown to enhance the opening of HCN channels by shifting their voltage-dependent activation toward depolarized potentials. The sea urchin HCN channel, SpIH, showed again a PIP2-mediated bidirectional effect but in reverse order than the depolarization-activated Cav and Kv channels: a voltage-dependent potentiation, like the mammalian HCN channels, but also an inhibition of the cGMP-induced current activation. Just like the Kv1.2 channels, distinct molecular determinants underlied the PIP2 dual effects on SpIH, with the proximal C-terminus implicated in the inhibitory effect. The dual regulation of these very different ion channels, all of which are voltage-dependent, points to conserved mechanisms of regulation of these channels by PIP2.

Phosphoinositide Control of Membrane Protein Function: A Frontier Led by Studies on Ion Channels

“…Similar mechanisms exert a dual effect on P/Q-type and N-type voltage-gated calcium channels in neurons (89, 90). Rodríguez-Menchaca et al (91, 92) and Abderemane-Ali et al (93) observed a similar dual effect for Kv1.2 and Shaker-like channels: PI(4,5)P 2 depletion left-shifted the voltage dependence of activation, increasing current while at the same time decreasing the open probability. These events decreased the current level.…”

“…These events decreased the current level. A dual effect was also seen in the sea urchin HCN channel, but in the reverse order (91). Kruse et al (94) tested a number of Kv channels in intact cells and found most of them to be insensitive to PI(4,5)P 2 ; this list includes Kv1.1/Kvβ1.1, Kv1.3, Kv1.4, Kv1.5/Kvβ1.3, Kv2.1, Kv3.4, Kv4.2, and Kv4.3 (with different Kv channel–interacting proteins).…”

Insulin Excites Anorexigenic Proopiomelanocortin Neurons via Activation of Canonical Transient Receptor Potential Channels

“…Activation of PI3K generates phosphatidylinositol-3,4,5-triphosphate (PIP 3 ), which appears to contribute to the translocation and activation of PLCγ at the plasma membrane (Bae et al, 1998; Falasca et al, 1998; Rameh et al, 1998). Through its phospholipase catalytic domains, PLCγ hydrolyzes PIP 2 , which affects multiple channels including TRPC channels (Rodríguez-Menchaca et al, 2012; Zhang et al., 2013). In addition, in hippocampal neuronal cultures, nerve growth factor and brain-derived neurotrophic factor activate PI3K and increase the rapid membrane insertion of TRPC5 channels from intracellular vesicular pools (Bezzerides et al, 2004), all of which also may be involved in actions of leptin and insulin in POMC neurons (Figure 6).…”

Insulin and leptin excite anorexigenic pro‐opiomelanocortin neurones via activation of TRPC5 channels

“…Activation of PI3K generates phosphatidylinositol‐3,4,5‐triphosphate, which appears to contribute to the translocation and activation of phospholipase C (PLC)γ at the plasma membrane . Through its phospholipase catalytic domains, PLCγ hydrolyses phosphatidylinositol 4,5‐bisphosphate, which affects multiple channels, including TRPC channels . In addition, in hippocampal neuronal cultures, nerve growth factor and brain‐derived neurotrophic factor activate PI3K and increase the insertion of TRPC5 channels into the plasma membrane from intracellular vesicular pools, all of which also may be involved in actions of insulin and leptin in POMC neurones.…”

“…[29][30][31] Through its phospholipase catalytic domains, PLCγ hydrolyses phosphatidylinositol 4,5-bisphosphate, which affects multiple channels, including TRPC channels. 32,33 In addition, in hippocampal neuronal cultures, nerve growth factor and brain-derived neurotrophic factor activate PI3K and increase the insertion of TRPC5 channels into the plasma membrane from intracellular vesicular pools, 34 all of which also may be involved in actions of insulin and leptin in POMC neurones. Because PI3K is essential for mediating the effects of leptin 14,16 and is also critical for the membrane insertion of TRPC channels, 34 we also examined the role of PI3K in the insulin-induced inward current.…”