The
cognitive dysfunction experienced by patients with
schizophrenia represents a major unmet clinical need. We believe that enhancing synaptic function and plasticity by targeting kalirin may provide a novel means to remediate these symptoms. Karilin (a
protein encoded by the KALRN gene) has multiple functional domains, including two Dbl homology (DH)
guanine exchange factor (GEF) domains, which act to enhance the activity of the Rho family
guanosine triphosphate (
GTP)-ases. Here, we provide an overview of kalirin's roles in brain function and its therapeutic potential in
schizophrenia. We outline how it mediates diverse effects via a suite of distinct
isoforms that couple to members of the
Rho GTPase family to regulate synapse formation and stabilisation, and how genomic and post-mortem data implicate it in
schizophrenia. We then review the current state of knowledge about the influence of kalirin on brain function at a systems level, based largely on evidence from transgenic mouse models, which support its proposed role in regulating dendritic spine function and plasticity. We demonstrate that, whilst the
GTPases are classically considered to be 'undruggable', targeting kalirin and other Rho GEFs provides a means to indirectly modulate their activity. Finally, we integrate across the information presented to assess the therapeutic potential of kalirin for
schizophrenia and highlight the key outstanding questions required to advance it in this capacity; namely, the need for more information about the diversity and function of its
isoforms, how these change across neurodevelopment, and how they affect brain function in vivo.