Pituitary Adenylate Cyclase Activating Peptide Phase Shifts Circadian Rhythms in a Manner Similar to Light

Abstract

The endogenous circadian pacemaker in mammals is located in the suprachiasmatic nuclei (SCN) of the hypothalamus. Various cues can reset circadian rhythm phase, thereby entraining the internal rhythm to the environmental cycle, and these effects can be investigated using an in vitro method to measure phase shifts of the SCN. Although pituitary adenylate cyclase activating peptide (PACAP) is localized in retinal inputs to the SCN, it has been reported to alter clock phase only during the subjective day (Hannibal et al., 1997), whereas light alters phase only in the subjective night. In this study we show that PACAP can reset the clock in the photic pattern during the subjective night when applied in 10 pM to 1 nM doses. This appears to be mediated via a glutamatergic mechanism, possibly by potentiation of NMDA currents as is seen at 10-100 pM. Given at higher doses (Ͼ10 nM), PACAP shifts in the subjective day, apparently via activation of adenylate cyclase and increased intracellular cAMP. These results indicate dose and phase specificity of the effects of PACAP, and a new role as a transmitter in the retinohypothalamic tract.

Pituitary adenylyl cyclase-activating peptide: A pivotal modulator of glutamatergic regulation of the suprachiasmatic circadian clock

“…Therefore, Glu is necessary to initiate the phase shift, but the level of PACAP participation alters the strength of the Glu signal. These observations are distinct from the recently reported effects of very low concentrations of PACAP, which appear to induce small phase changes via a non-cAMP-mediated mechanism that involves potentiation of the NMDA receptor (26), rather than crosstalk among second messengers. Together, these observations reveal a range of PACAP-Glu interactions that are significant in view of their colocalization in retinal ganglion cells that innervate the SCN (15).…”

Regulation of Pituitary Adenylate Cyclase-activating Polypeptide Gene Transcription by TTF-1, a Homeodomain-containing Transcription Factor

“…Photic cues are transmitted to the SCN via the retinohypothalamic tract (RHT) (32) and entrain the SCN and its output rhythms to a 24-h day cycle. PACAP is abundant in the rat SCN, the RHT, and retinal ganglionic cells (32,33), and it has been shown to reset the circadian clock in a manner similar to light (34,35). Taken together, these reports suggest an involvement of PACAP in the regulation of central circadian rhythm in the mammalian SCN.…”

Long-term effects of neonatal alcohol exposure on photic reentrainment and phase-shifting responses of the activity rhythm in adult rats

“…The putative photopigment, melanopsin, and the neurotransmitters, glutamate and pituitary adenylate cyclase-activating polypeptide (PACAP), are thought to mediate the communication of light information to the SCN because (1) melanopsin is distinctly localized in retinal ganglion cells that are endogenously responsive to light (Hattar et al, 2002); (2) glutamate and PACAP have been identified as the principal neurotransmitters of the RHT (De Vries et al, 1993;Hannibal et al, 2000;van den Pol, 1993); (3) transgenic deletion of genes encoding melanopsin, PACAP, and PACAP receptors influences the phase-shifting responses of the murine circadian clock to light (Colwell et al, 2004;Hannibal et al, 2001;Harmar et al, 2002;Ruby et al, 2002); and (4) infusion of glutamate or PACAP into the SCN phase shifts circadian rhythms in a manner comparable to light (Harrington et al, 1999;Meijer et al, 1988). Thus, neonatal EtOH exposure may chronically increase both the entraining and phaseshifting effects of light on the SCN clock by enhancing melanopsin-mediated phototransduction or by potentiating glutamate and/or PACAP function in the communication of photic signals to the SCN.…”