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Fig. 6.4 Model of kisspeptin's actions to depolarize GnRH neurons and facilitate burst fi ring.
Kisspeptin binds to its cognate GPR54 receptor, which is Gq-coupled to activate phospholipase
Cβ. PLCβ has multiple downstream actions resultant from cleaving phosphatidylinositol 4,5
bisphosphate (PIP 2 ) to inositol 1,4,5-triphosphate (IP 3 ) and diacylglycerol (DAG). Since PIP 2
facilitates Kir channel opening, cleavage of this fatty acid attenuates K-ATP and GIRK channel
opening. Inhibition of GIRK channels renders a number of Gα i/o -coupled receptors ineffective
to inhibit GnRH neurons (GABA B , μ-opioid, NPY, MCH, etc.). On the other hand, cleavage of
PIP 2 facilitates TRPC 4 channel opening [ 126 ]. In addition the membrane-associated fatty acid
DAG probably activates the TRPC1, 4, 5 channel complex [Note: The OAG (analogue of DAG)
was only weakly effective to open the TRPC channels since PIP 2 still exerted a strong inhibi-
tion of the TRPC channel complex]. Ca 2+ potentiates the agonist-activated TRPC1, 4, 5 com-
plex, and plasma membrane calcium channels appear to play a critical role. Intracellular 2-APB
dialysis, which effectively blocks IP3 receptor-mediated release of Ca 2+ , was ineffective, but
extracellular Cd 2+ potently inhibited TRPC1, 4, 5 channel activity. Therefore, we propose that
low voltage-activated T-type calcium channels are initially involved in facilitating TRPC chan-
nel opening. Once depolarized, Ca 2+ entry through high voltage-activated Ca 2+ channels can
also contribute to facilitating TRPC channel opening. Also illustrated are other channels con-
tributing to burst fi ring activity such as the hyperpolarization-activated, cyclic nucleotide-gated
(HCN, pacemaker) channel, and the small conductance, Ca 2+ -activated K + channel (SK), which
is involved in the repolarization of the membrane following a burst of action potentials
desensitize (i.e., heterologous desensitization) G
i/o -coupled receptors through PIP 2
hydrolysis and attenuating the GIRK-mediated hyperpolarization (Fig. 6.4 ) [ 97 -
99 ]. In addition to attenuating G
α
i/o -coupled receptor-mediated hyperpolarization,
kisspeptin activates TRPC channels in GnRH neurons to cause further depolariza-
tion [ 14 ]. The Kiss1R-G
α
signaling pathway would have a twofold effect
to inhibit K + channels and activate TRPC channels, which underlies the pronounced
excitatory effects of kisspeptin on GnRH neurons [ 12 - 14 , 50 , 52 ]. Interestingly
MCH, although at higher concentrations, can block kisspeptin excitation of septal
vesicular glutamate transporter 2 (vGluT2)-GnRH neurons by inhibiting Kir [ 55 ],
which could be a mechanism by which GnRH neuronal excitability is reduced dur-
ing certain physiological states.
α
q/11 -PLC
β
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