Beyond the Brain: GABAergic Signaling as a Peripheral Modulator of Skin Barrier Immunity

Beyond its canonical role as the principal inhibitory neurotransmitter in the central nervous system (CNS), peripheral GABAergic signaling has emerged as an important regulator of skin barrier immunity and tissue homeostasis. This review synthesizes current evidence on the expression, distribution, and function of both GABA-A and GABA-B receptors in keratinocytes, fibroblasts, melanocytes, sensory neurons, and cutaneous immune cells, including Langerhans cells, macrophages, mast cells, and T lymphocytes. Particular emphasis is placed on how GABAergic signaling regulates ion transport, calcium dynamics, epidermal differentiation, and immune homeostasis through coordinated interactions with ion channels within the broader cutaneous neuro-immuno-endocrine network. We further discuss evidence supporting the role of cutaneous GABAergic signaling in maintaining barrier integrity, modulating inflammatory responses, and contributing to skin–brain communication within the broader cutaneous neuro-immuno-endocrine network under physiological and pathological conditions. Finally, we summarize the therapeutic potential of targeting peripheral GABAergic pathways in atopic dermatitis, psoriasis, chronic pruritus, photoaging, and other stress-associated dermatoses, highlighting their promise as novel therapeutic strategies in precision dermatology.