THE CADHERIN SUPERFAMILY: BIOLOGICAL SIGNIFICANCE AND NEUROLOGICAL DIVERSITY
Zaharieva I*
*Corresponding Author: Dr. Irina Zaharieva, Department of Medical Genetics, Medical University Sofia, 2 Zdrave str, 1431 Sofia, Bulgaria; Tel./Fax: +359-2-952-03-57; E-mail: irinazaharieva@yahoo.co.uk
page: 19

CADHERIN SUPERFAMILY PROTEINS IN SYNAPSES

Neurons communicate with each other via synapses. The synapses have two main tasks. First, they are responsi­ble for the flow of information from one neuron to an­other. Second, the synapses act as a control panel that decides which neurons are connected and these connec­tions are not random, but specific. Sperry [27] suggests that the selection is accomplished by specific recognition sites residing in the pre- and post-synaptic membranes, fitting together like a ‘lock and key’. According to this theory, different nerve fiber types are guided to their respective end organs and other connections sites by selec­tive molecules. The patterns of synaptic connections in the nerve centers must be handled with very strict selectivity governing synaptic formation from the beginning. The establishment and maintenance of synaptic associations are regulated by highly specific cytochemical affinities. These cytochemical affinities arise systematically among the different types of neurons. Neurons in the brain and cord carry some kind of individual identification tags by which they are distinguished one from another to the level of the single neuron. Each axon links only with certain neurons to which it becomes selectively attached by spe­cific chemical affinities [27].

      Classical cadherins and associated catenins were found in synapses in the zones bordering the active zone. Each of these classic cadherins has selective binding activ­ities for regulation specific interneuronal connections. The protocadherins are also expressed in synapses. In different synapses different protocadherins are found. The binding between protocadherins is specific and homophilic, which means that a particular protocadherin protein at the pre­synaptic membrane can bind to the same protocadherin protein at the post-synaptic membrane. Thus, the specific­ity of each synapse will be determined by protocadherin homodimers.

      The rearrangement between V- and C-regions in proto­cadherins gives rise to different types protocadherins according to which type of V-gene is translocated to the C-gene. The translocation is irreversible and the translated V-gene will never be exchanged for another V-gene. The α-V-gene translocation leads to 15 different types of Pcdh-α  protein, V-gene translocation of the β-protocadherins also leads to 15 different variants and γ-protocadherin V-gene rearranges to 22 variants. Each neuron has a different combination of protocadherins expressed at three sites: α, β and γ. Each neuron can form homophilic contacts in three directions with other neurons via protocadherins. By doing this, the neurons organize themselves into a neuron­al network in which each synapse contacts the recognition sites for another neuron [28].

      The following hypotheses of abnormalities in synaptic connectivity and plasticity in the pathophysiology of schizophrenia have been suggested by our team [29]. It has been proposed that schizophrenia might, in part, be a dis­order caused by a defect in the development of synaptic connectivity and therefore protocadherins are good func­tional candidate genes [30]. This group of genes and their relation to schizophrenia has been investigated by several research groups [30-33] and none of these could confirm the contribution of polymorphisms in protocadherin genes to schizophrenia susceptibility. Thus, further analyses of the protocadherins and catherins may reveal novel molec­ular mechanisms underlying psychiatric diseases.

 




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