The puzzling role of TRPC3 channels in motor coordination

Transient receptor potential canonical 3 (TRPC3) proteins are nonselective cation channels activated downstream of phospholipase-C-coupled receptors. TRPC3 channels have emerged as major players in the function of the central nervous system. They have been described as important contributors to brain-derived neurotrophic factor mediated survival and growth-cone guidance of cerebellar granule neurons. TRPC3 were also identified as postsynaptic cation channels essential for metabotropic glutamate receptor1-dependent synaptic transmission in cerebellar Purkinje neurons. A recent report described motor coordination defects in TRPC3 knockout mice while a subsequent study reported a similar phenotype in so-called moonwalker mice, harboring a TRPC3 gain-of-function mutation. How can opposing aspects of TRPC3 channel activation lead to the same phenotype? Here we discuss the salient features of TRPC3 knockout mice and moonwalker mice and attempt to reconcile the apparently conflicting findings from these two animal models.