Constitutive and ghrelin-dependent GHSR1a activation impairs CaV2.1 and CaV2.2 currents in hypothalamic neurons.
The growth hormone secretagogue receptor type 1a (GHSR1a) has the highest known constitutive activity of any G protein-coupled receptor (GPCR). GHSR1a mediates the action of the hormone ghrelin, and its activation increases transcriptional and electrical activity in hypothalamic neurons. Although GHSR1a is present at GABAergic presynaptic terminals, its effect on neurotransmitter release remains unclear. The activities of the voltage-gated calcium channels, CaV2.1 and CaV2.2, which mediate neurotransmitter release at presynaptic terminals, are modulated by many GPCRs. Here, we show that both constitutive and agonist-dependent GHSR1a activity elicit a strong impairment of CaV2.1 and CaV2.2 currents in rat and mouse hypothalamic neurons and in a heterologous expression system. Constitutive GHSR1a activity reduces CaV2 currents by a Gi/o-dependent mechanism that involves persistent reduction in channel density at the plasma membrane, whereas ghrelin-dependent GHSR1a inhibition is reversible and involves altered CaV2 gating via a Gq-dependent pathway. Thus, GHSR1a differentially inhibits CaV2 channels by Gi/o or Gq protein pathways depending on its mode of activation. Moreover, we present evidence suggesting that GHSR1a-mediated inhibition of CaV2 attenuates GABA release in hypothalamic neurons, a mechanism that could contribute to neuronal activation through the disinhibition of postsynaptic neurons.
Laboratory of Electrophysiology and Laboratory of Neurophysiology, Multidisciplinary Institute of Cell Biology (IMBICE), B1904CMA La Plata, Buenos Aires, Argentina.
Eduardo Javier
EJ
López Soto
Laboratory of Electrophysiology and Laboratory of Neurophysiology, Multidisciplinary Institute of Cell Biology (IMBICE), B1904CMA La Plata, Buenos Aires, Argentina.
Francina
F
Agosti
Laboratory of Electrophysiology and Laboratory of Neurophysiology, Multidisciplinary Institute of Cell Biology (IMBICE), B1904CMA La Plata, Buenos Aires, Argentina.
Agustina
A
Cabral
Laboratory of Electrophysiology and Laboratory of Neurophysiology, Multidisciplinary Institute of Cell Biology (IMBICE), B1904CMA La Plata, Buenos Aires, Argentina.
Emilio Roman
ER
Mustafa
Laboratory of Electrophysiology and Laboratory of Neurophysiology, Multidisciplinary Institute of Cell Biology (IMBICE), B1904CMA La Plata, Buenos Aires, Argentina.
Valentina Martínez
VM
Damonte
Department of Cell Biology, Center for Research and Advanced Studies of the National Polytechnic Institute, 07000 México D.F., México.
Maria Alejandra
MA
Gandini
Laboratory of Electrophysiology and Laboratory of Neurophysiology, Multidisciplinary Institute of Cell Biology (IMBICE), B1904CMA La Plata, Buenos Aires, Argentina.
Silvia
S
Rodríguez
Laboratory of Electrophysiology and Laboratory of Neurophysiology, Multidisciplinary Institute of Cell Biology (IMBICE), B1904CMA La Plata, Buenos Aires, Argentina Laboratory of Electrophysiology and Laboratory of Neurophysiology, Multidisciplinary Institute of Cell Biology (IMBICE), B1904CMA La Plata, Buenos Aires, Argentina.
Daniel
D
Castrogiovanni
Department of Cell Biology, Center for Research and Advanced Studies of the National Polytechnic Institute, 07000 México D.F., México.
Ricardo
R
Felix
Laboratory of Electrophysiology and Laboratory of Neurophysiology, Multidisciplinary Institute of Cell Biology (IMBICE), B1904CMA La Plata, Buenos Aires, Argentina.
Mario
M
Perelló
Laboratory of Electrophysiology and Laboratory of Neurophysiology, Multidisciplinary Institute of Cell Biology (IMBICE), B1904CMA La Plata, Buenos Aires, Argentina jraingo@imbice.gov.ar.
Jesica
J
Raingo
D000818:Animals; D001483:Base Sequence; D002118:Calcium / Q000378:metabolism; D020864:Calcium Channels, N-Type / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology; D002478:Cells, Cultured; D054439:Ghrelin / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007031:Hypothalamus / Q000502:physiology*; D015640:Ion Channel Gating / Q000502:physiology; D051379:Mice; D008969:Molecular Sequence Data; D009474:Neurons / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D054440:Receptors, Ghrelin / Q000235:genetics / Q000378:metabolism*
D002118:Calcium; D020864:Calcium Channels, N-Type; D054439:Ghrelin; D054440:Receptors, Ghrelin; C503279:Cacna1b protein, rat; C571124:Ghsr1a protein, rat