Insulin Activates Native and Recombinant Large Conductance Ca²⁺-Activated Potassium Channels via a Mitogen-Activated Protein Kinase-Dependent Process

Abstract

Evidence is accumulating that, in addition to regulating peripheral energy metabolism, insulin is an important modulator of neuronal function. Indeed, high levels of insulin and insulin receptors are expressed in several brain regions including the hippocampus. We have shown previously that insulin inhibits aberrant synaptic activity in hippocampal neurons via activation of large conductance Ca 2ϩ -activated K ϩ (BK) channels. In this study, we have examined further the effects of insulin on native hippocampal and recombinant (hSlo) BK channels expressed in human embryonic kidney (HEK) 293 cells. Pipette or bath application of insulin evoked a rapid increase in hippocampal BK channel activity, an action caused by activation of insulin receptors because insulin-like growth factor 1 (IGF-1) failed to mimic insulin action. In parallel studies, insulin, applied via the pipette or bath, also activated hSlo channels expressed in HEK293 cells. Although phosphoinositide 3-kinase is a key component of insulin and IGF-1 receptor signaling pathways, activation of this lipid kinase does not underlie the effects of insulin because neither 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002) nor wortmannin inhibited or reversed insulin action. However, specific inhibitors of mitogenactivated protein kinase (MAPK) activation, 2Ј-amino-3Ј-methoxyflavone (PD98059) or 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)-butadiene (U0126), attenuated insulin action, indicating that a MAPK-dependent mechanism underlies this process. Furthermore, insulin activation of this pathway enhances BK channel activity by shifting the Ca 2ϩ -sensitivity such that BK channels are active at more hyperpolarized membrane potentials. Because postsynaptic BK channels are important regulators of neuronal hyperexcitability, insulin-induced activation of BK channels, via stimulation of a MAPK-dependent pathway, may be an important process for regulating hippocampal function under normal and pathological conditions.

KCNMA1 gene amplification promotes tumor cell proliferation in human prostate cancer

“…Serum and glucocorticoid-inducible kinase, phosphoinositide-3 kinase and the mitogen-activated protein kinase pathway are activated by serum and have been shown to stimulate BK channels (Henke et al, 2004;O'Malley and Harvey, 2004). The role of estrogens in prostate cancer is controversial and is also challenged by the present results.…”

“…Taken together, activation of BK channel might be a major target of 17b-estradiol in prostate cancer in the absence of KCNMA1 amplification and overexpression. However, it is likely that BK channels are modulated by a complex network of different molecules and molecular pathways (O'Malley and Harvey, 2004;Olsen et al, 2005).…”

Leptin Contributes to Slower Weight Gain in Juvenile Rodents on a Ketogenic Diet

“…Leptin can act as an anticonvulsant throughout the brain because leptin receptors exist throughout the brain (28) and activate calcium-activated potassium channels (9). However, the decline in insulin may counteract some of the effects of the rise in leptin because insulin activates the same channel (10). In summary, we hypothesize that the KD produces a net anticonvulsant effect in part because increased brain leptin activates potassium channels.…”

Insulin receptor regulates photoreceptor CNG channel activity

“…Phosphorylation of CNG channels has been shown to control its function in several studies (18,24,26), but a detailed study about the residues involved and the responsible protein kinase(s) has not been done so far. Insulin-induced modulation of several ion channels has been reported earlier (8,16,28), but no studies are available on the direct involvement of IR in the regulation of ion channels. Tyrosine residue 498 has previously been shown to be tyrosine phosphorylated and is implicated in the modulation of CNG channel activity (18); however, the actual kinase that phosphorylates this residue has not been indentified.…”