Phoenixin

Phoenixin activates GPR173, an orphan GPCR now recognized as the phoenixin receptor, coupled to Gs proteins and cAMP elevation. In the hypothalamus, GPR173 activation modulates GnRH neuron activity and kisspeptin signaling, regulating LH pulsatility. GPR173 is also expressed in the limbic system (amygdala, hippocampus), where phoenixin modulates anxiety circuits and memory consolidation.

Phoenixin promotes GnRH release from hypothalamic neurons and enhances kisspeptin-stimulated LH secretion. ICV phoenixin in female rats increases LH pulse amplitude and frequency, and phoenixin antagonism disrupts the preovulatory LH surge. These findings suggest phoenixin plays a facilitatory role in reproductive axis activation during the transition from negative to positive estrogen feedback.

ICV phoenixin-14 produced anxiolytic-like effects in the elevated plus maze and light-dark box in rodents. The amygdala, expressing high levels of GPR173, appears to mediate these effects through modulation of GABAergic tone. Phoenixin levels correlate inversely with anxiety-like behavior, suggesting an endogenous anxiolytic role.

Phoenixin enhanced memory performance in the novel object recognition test and Morris water maze. Hippocampal GPR173 activation is thought to promote synaptic plasticity through BDNF upregulation and ERK/CREB signaling. These findings add phoenixin to the growing list of hypothalamic-derived peptides with cognitive effects.

Peripheral phoenixin injection reduced inflammatory pain responses in rodent models. Mechanistic studies suggest phoenixin suppresses NF-kB activation and reduces pro-inflammatory cytokine production at peripheral GPR173. Phoenixin plasma levels are reduced in chronic pain patients in some preliminary human studies.