Related Experiment Videos
IGF-1 modulates N and L calcium channels in a PI 3-kinase-dependent manner
1Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520-8066, USA.
Abstract:
Receptor tyrosine kinases (RTKs) have long been associated with proliferation in non-neural cells, although they are also expressed in postmitotic neurons. We demonstrate that insulin-like growth factor-1 (IGF-1) induces within seconds a large, tyrosine-kinase-dependent increase in calcium channel currents in cerebellar granule neurons. Separation of channel subtypes reveals that, while P, Q, and R channels are unaffected, N and L channel activities are strongly potentiated at specific membrane voltages: N currents triple at depolarized potentials, while L currents rapidly increase 4-fold at hyperpolarized potentials. Moreover, transient expression of dominant-negative and wild-type phosphatidylinositol 3-OH kinase (PI 3-kinase) subunits, as well as application of specific inhibitors, demonstrates that PI 3-kinase is an essential and rate-limiting messenger in this signaling pathway. Our results indicate that N and L calcium channels are downstream targets of neuronal RTKs and suggest that RTK modulation may control calcium-dependent processes, such as neurotransmitter release and IGF-1-dependent differentiation or survival.
Insights
Insulin-like growth factor-1 (IGF-1) rapidly enhances N and L calcium channel activity in neurons via receptor tyrosine kinases (RTKs) and phosphatidylinositol 3-OH kinase (PI 3-kinase). This suggests RTK signaling regulates crucial calcium-dependent neuronal functions.
Area of Science:
- Neuroscience
- Cellular Signaling
- Molecular Biology
Background:
- Receptor tyrosine kinases (RTKs) are known regulators of cell proliferation.
- RTKs are also present in postmitotic neurons, suggesting roles beyond cell division.
- The specific functions of RTKs in mature neurons remain to be fully elucidated.
Purpose of the Study:
- To investigate the rapid effects of insulin-like growth factor-1 (IGF-1) on neuronal ion channel activity.
- To determine the role of receptor tyrosine kinases (RTKs) and phosphatidylinositol 3-OH kinase (PI 3-kinase) in IGF-1-mediated signaling in neurons.
- To identify the specific calcium channel subtypes modulated by RTK signaling.
Main Methods:
- Electrophysiological recordings of calcium channel currents in cerebellar granule neurons.
- Utilized dominant-negative and wild-type PI 3-kinase subunits for functional studies.
- Employed specific PI 3-kinase inhibitors to block signaling pathways.
Main Results:
- IGF-1 induced a rapid, tyrosine-kinase-dependent increase in calcium channel currents.
- N-type calcium currents tripled at depolarized potentials, and L-type calcium currents quadrupled at hyperpolarized potentials.
- PI 3-kinase was identified as an essential, rate-limiting messenger in this signaling cascade.
Conclusions:
- Neuronal RTKs directly modulate N and L type calcium channels.
- RTK signaling pathways, involving PI 3-kinase, are critical for regulating neuronal calcium homeostasis.
- This modulation of calcium channels by RTKs may control essential neuronal processes like neurotransmitter release and cell survival.