Identifying roles for peptidergic signaling in mice

Area of Science:

• Biochemistry
• Neuroscience
• Molecular Biology

Background:

• Neuropeptides are vital signaling molecules, but their complex signaling pathways hinder therapeutic development.
• Peptidylglycine α-amidating monooxygenase (PAM) is essential for neuropeptide amidation, a critical step for biological activity.
• Global PAM deficiency is lethal, necessitating conditional knockout models to study its specific functions.

Purpose of the Study:

• To investigate the physiological roles of PAM by creating cell type-specific knockout mice.
• To identify tissue-specific deficits and behavioral changes resulting from the elimination of PAM expression.

Main Methods:

• Generation of conditional Pam knockout mice with cell type-specific deletion of PAM.
• Phenotypic screening of knockout mice for behavioral and physiological alterations.
• RNA sequencing to analyze gene expression changes in affected tissues.

Main Results:

• Eliminating PAM in forebrain neurons reduced anxiety, increased cocaine responsiveness, and improved cold thermoregulation.
• Deleting PAM in cardiomyocytes increased anxiety and improved thermoregulation, with decreased atrial natriuretic peptide (ANP) levels.
• RNA sequencing revealed altered gene expression related to cardiac function in cardiomyocyte-specific knockouts.

Conclusions:

• Cell type-specific PAM deletion is a viable screening platform for identifying neuropeptide pathway functions.
• PAM plays critical, distinct roles in neuronal and cardiac function.
• This approach can facilitate the development of targeted therapeutics for peptidergic signaling.