Kisspeptin Excitation of GnRH Neurons - Kisspeptin Signaling in Reproductive Biology - page 114

some of the recordings performed by Dumalska and coworkers were made from
animals as young as 15 days of age [ 51 ], so the reduced response to kisspeptin could
be age-related. Although the expression of Kiss1R is similar in juvenile as in adult
male mice, and at both age levels Kiss1R can be detected in over 90% of GnRH
neurons [ 12 ], the percent of GnRH neurons responding to kisspeptin is only about
27% in juvenile vs. 90% in adult males [ 12 ]. The reason for the reduced effi cacy of
kisspeptin in GnRH neurons from juvenile and prepubertal males is not fully under-
stood but could be due to an immature Kiss1R signaling in the younger animals.
In the adult, kisspeptin depolarizes GnRH neurons via the coupling of Kiss1R
to a phospholipase C

) signaling pathway that activates canonical transient
receptor potential (TRPC) channels that allow infl ux of sodium and to a lesser
extent calcium ions (Fig. 6.2 ) [ 14 ]. Besides activating TRPC channels in GnRH
neurons, kisspeptin also attenuates resting and ligand-activated inwardly rectify-
ing K + (Kir) channels and A-type potassium channels [ 13 , 14 , 50 , 52 ]. The inhibi-
tion of Kir may be critical because Kir channels (e.g., K AT P and GIRK channels)
are highly expressed in GnRH neurons and clamp the cells in a negative resting
state of −63 mV [ 40 , 53 , 54 ]. This effect of kisspeptin is also vital for inhibiting
GPCR- activated (

β (PLC β

-opioid, GABA B and perhaps melanin-concentrating hormone,
MCH) GIRK (Kir) currents which are prominent in GnRH neurons [ 40 , 54 , 55 ].
Also, A-type K + currents are very prominent in GnRH neurons, and E 2 regulation
of the A-current may play a role in negative feedback regulation of GnRH neurons
[ 52 , 56 ]. Therefore, kisspeptin inhibition of these K + currents would be of high
functional signifi cance. Moreover, kisspeptin increases calcium oscillations of
mature as well as developing GnRH neurons, and these changes for the most part
refl ect the coupling of Kiss1R to a PLC

μ

signaling pathway [ 14 , 50 , 57 , 58 ].
Therefore, by inhibiting potassium channels along with the pronounced activation
of TRPC channels, kisspeptin depolarizes GnRH neurons to threshold (~−45 mV)
and induces sustained fi ring, which may be accompanied by a sustained calcium
ion infl ux via calcium channels/TRPC channels and augmented GnRH release
during positive feedback.

β

Kisspeptin Activation of TRPC Channels

The mammalian TRPC channel family consists of seven members, TRPC1-7, that
appear to function as receptor-operated channels, analogous to the TRP channels
involved in Drosophilia phototransduction [ 59 ]. With the exception of TRPC2,
these channels are widely distributed in the mammalian brain [ 60 ]. The TRP chan-
nels are made of subunits with six membrane-spanning domains that co-assemble as
tetrameric complexes similar to what has been described for K + channels [ 61 , 62 ].
TRPC channels appear to co-assemble as heteromeric channels consisting of the
TRPC1, 4, and 5 subfamily [ 63 , 64 ], as well as TRPC3, 6, and 7 subfamily [ 65 , 66 ].
It is well known that the current-voltage relationship and mechanisms of regulation
of TRPC channels depend on the channel subunit composition [ 59 ]. However, the