GnRH-1 neuronal activity is independent of HCN channels but is sensitive to PKA-dependent phosphoryl
March 29th, 2008 | by admin |GnRH-1 neuronal activity is independent of HCN channels but is sensitive to PKA-dependent phosphorylation.
Pulsatile release of gonadotropin-releasing hormone-1 (GnRH-1) stimulates the anterior pituitary and induces secretion of gonadotropin hormones. GnRH-1 release is modulated by many neurotransmitters that act via G protein-coupled membrane receptors. cAMP is the most ubiquitous effector for these receptors. GnRH-1 neurons express hyper-polarization-activated cyclic nucleotide-modulated channel (HCN) protein in vivo. HCN channels are involved in neuronal pacemaking and can integrate cAMP signals. cAMP-dependent protein kinase (PKA) is also activated by cAMP signals and PKA-dependent phosphorylation modulates voltage-activated channels. In this report, these two pathways were examined in GnRH-1 neurons as integrators of forskolin (FSK)-induced stimulation. The HCN3 isoform was detected in GnRH-1 neurons obtained from mouse nasal explants. ZD7288, a HCN channel blocker, significantly reduced the efficiency of FSK to stimulate GnRH-1 neurons while blockade of PKA with Rp-cAMPS did not attenuate the FSK-induced stimulation. To ensure that disruption of HCN channels on GnRH-1 neurons was responsible for reduction of FSK stimulation, experiments were performed removing GABA, the major excitatory input to GnRH-1 neurons in nasal explants. Under these conditions, Rp-cAMPS, but not ZD7288, altered the FSK-induced response of GnRH-1 neurons. These studies indicate that PKA-dependent phosphorylation is involved in the FSK-induced stimulation of GnRH-1 neurons rather than HCN channels and HCN channels integrate the FSK-induced stimulation on GABAergic neurons. In addition, blockade of HCN channels did not modify basal GnRH-1 neuronal activity when GABAergic input was intact or removed, negating a role for these channels in basal GABAergic or GnRH-1 neuronal activity.
Constantin S, Wray S.
Cellular and Developmental Neurobiology Section, NINDS / NIH, Bethesda MD 20892, USA.