Sex-specific cell signaling: the corticotropin-releasing factor receptor model

• Receptor signaling can be sex biased such that different pathways are engaged in males and females.
• The CRF receptor is an example of a receptor that exhibits sex biased signaling.
• Sex biased signaling may underlie sex differences in disease vulnerability and drug sensitivity.
• Sex biased signaling underscores the importance of including both sexes in biomedical research.

Elucidating the biological basis for sex differences in diseases can reveal their pathophysiology and guide the development of individualized treatments. Here, we review evidence for the novel concept that receptor signaling can be sex biased such that the specific pathways engaged by ligand binding are determined by sex. As an example, this review focuses on the receptor for corticotropin-releasing factor (CRF), a stress-related peptide implicated in diverse psychiatric and medical disorders that are more prevalent in females. There is evidence for sex biases in CRF receptor coupling to G proteins and β-arrestin that render females more sensitive to acute stress and less able to adapt to chronic stress. Taken with evidence for sex biased signaling in other receptor systems, the studies demonstrate the broad potential impact of this characteristic in determining sex differences in disease and therapeutic efficacy and underscore the importance of studying females in medical and pharmacological research.