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neurons, the TRPC1, 4, and 5 family appear to be major (key) players in mediat-
ing the effects of kisspeptin in GnRH neurons [ 14 ].
Kisspeptin Inhibition of Kir Channels and Their Role
in GnRH Neuronal Excitability
Kisspeptin augments the activity of GnRH neurons in part via inhibition of Kir
potassium channels [ 13 , 14 , 50 ]. In this respect, the Kir blockers barium (0.3 mM)
and tetraethylammonium (20 mM) robustly inhibit the kisspeptin-induced potas-
sium currents in GnRH neurons [ 13 , 14 , 50 ]. The importance of kisspeptin inhibi-
tion of Kir is further substantiated by the ability of kisspeptin to attenuate the
GABA B -induced hyperpolarization in GnRH neurons [ 54 ].
GABA is one of the most important neurotransmitters that regulate the excitabil-
ity of GnRH neurons. Multiple studies have shown that GABA activates Cl cur-
rents in GnRH neurons, and these effects are blocked by GABA A receptor antagonists
[ 44 , 46 , 47 , 76 - 78 ]. It is generally accepted that activation of GABA A receptors
depolarizes and excites GnRH neurons [ 46 , 78 - 80 ]. Several GABA A receptor sub-
units have been identifi ed in GnRH neurons, including
α
1,
α
2,
α
3,
α
5,
β
1,
β
2,
β
3,
γ
2, and the rho 1 subunits [ 78 , 81 , 82 ]. The GABA B receptor subunits, R1 and
R2, are also found in GnRH neurons [ 54 , 83 ], and GABA activates GABA B -
receptors in GnRH neurons [ 54 , 84 ]. Moreover, as has been demonstrated in numer-
ous other hypothalamic neurons [ 85 - 90 ], GABA B receptors are coupled (G
1,
γ
i/o ) to
activation of G protein-coupled inwardly rectifying K + (GIRK) channels, resulting
in a robust hyperpolarization of GnRH neurons.
The importance of Kir channels in modulating GnRH neuronal excitability has
been well documented [ 13 , 14 , 40 , 53 - 55 , 84 ]. Female GnRH neurons sit at a rela-
tively negative resting membrane potential (−63 mV) that is due, in part, to the
activity of Kir channels including GIRKs and K AT P channels [ 53 , 54 ]. For example,
blocking the K AT P channels with the sulfonylurea tolbutamide signifi cantly depolar-
izes the cells by 4-6 mV, which puts the membrane potential in the range of most
parvocellular hypothalamic neurons [ 53 , 91 ]. In addition, GABA release is regu-
lated by E 2 through presynaptic mechanisms [ 85 , 87 , 92 - 94 ] that affect GnRH neu-
ronal activity [ 40 , 95 ]. Augmented E 2 -induced GABA B receptor activity would
further hyperpolarize the membrane through increased GIRK channel activity.
However, this inhibitory tone must be attenuated during the excitatory (preovula-
tory) phase of GnRH neurons. One possible mechanism is that kisspeptin signaling
via KissR provides the stimulus to overcome this strong inhibitory tone (Fig. 6.4 ).
Previous investigators have shown that there is a robust kisspeptin drive during E 2
“positive feedback” [ 13 , 15 , 96 ], and kisspeptin counters the hyperpolarizing effects
of activation of GIRKs by the GABA B agonist baclofen,
α
-opioid receptor agonists
(Zhang et al., unpublished fi ndings), and other Ba 2+ -sensitive inwardly rectifying K +
channels in general [ 13 , 14 ]. Moreover, G
μ
α
q/11 -coupled receptors are known to
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