Ghrelin Selectively Inhibits CaV3.3 Subtype of Low-Voltage-Gated Calcium Channels
The mechanisms by which ghrelin controls electrical activity in the hypothalamus are not fully understood. One unexplored target of ghrelin is Ca<sub>V</sub>3, responsible for transient calcium currents (T-currents) that control neuronal firing. We investigated the effect of ghrelin on C...
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| Autores principales: | , , |
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| Formato: | Articulo |
| Lenguaje: | Inglés |
| Publicado: |
2020
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| Materias: | |
| Acceso en línea: | http://sedici.unlp.edu.ar/handle/10915/130925 |
| Aporte de: |
| Sumario: | The mechanisms by which ghrelin controls electrical activity in the hypothalamus are not fully understood. One unexplored target of ghrelin is Ca<sub>V</sub>3, responsible for transient calcium currents (T-currents) that control neuronal firing. We investigated the effect of ghrelin on Ca<sub>V</sub>3 subtypes and how this modulation impacts on neuronal activity. We performed whole-cell patch-clamp recordings in primary mouse hypothalamic cultures to explore the effect of ghrelin on T-currents. We also recorded calcium currents from transiently transfected tsA201 cells to study the sensitivity of each Ca<sub>V</sub>3 subtype to GHSR activation. Finally, we ran a computational model combining the well-known reduction of potassium current by ghrelin with the Ca<sub>V</sub>3 biophysical parameter modifications induced by ghrelin to predict the impact on neuronal electrical behavior. We found that ghrelin inhibits native NiCl₂ sensitive current currents in hypothalamic neurons. We determined that Ca<sub>V</sub>3.3 is the only Ca<sub>V</sub>3 subtype sensitive to ghrelin. The modulation of Ca<sub>V</sub>3.3 by ghrelin comprises a reduction in maximum conductance, a shift to hyperpolarized voltages of the I–V and steady-state inactivation curves, and an acceleration of activation and inactivation kinetics. Our model-based prediction indicates that the inhibition of Ca<sub>V</sub>3.3 would attenuate the stimulation of firing originating from the inhibition of potassium currents by ghrelin. In summary, we discovered a new target of ghrelin in neurons: the Ca<sub>V</sub>3.3. This mechanism would imply a negative feed-forward regulation of the neuronal activation exerted by ghrelin. Our work expands the knowledge of the wide range of actions of GHSR, a receptor potentially targeted by therapeutics for several diseases. |
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