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L-type Calcium channels in health and disease

Final Activity Report Summary - CAVNET (L-type Calcium Channels in Health and Disease)

Amongst the great variety of ion channels in our body, a specialised group of calcium channels (L-type voltage-gated Ca2+ channels or L-VGCCs) represent well-established therapeutic targets to treat hypertension or ischemic heart diseases. L-VGCCs also exist outside the cardiovascular system, e.g. in the adrenal gland, inner ear, pancreas and brain, controlling functions such as stress, hearing, insulin secretion or e.g. memory. Therefore, an isoform-specific pharmaceutical Ca-channel targeting for future treatment of cumulative diseases such as diabetes, Alzheimer, Parkinson, hearing loss or stress-disorders would be highly attractive. Currently, selective targeting is impossible as the distinct subtypes Cav1.2 and Cav1.3 cannot be functionally distinguished. To tackle this crucial problem, the training network CAVNET unified renowned specialists for the different organs (heart, pancreas, adrenal gland, auditory system, brain).

In a joint attempt to investigate the distinct functions of Cav1.2 and Cav1.3 young researchers were offered a comprehensive training program that included not only their individual research projects and accompanying curricula but also training in interdisciplinary experimental methods at various scientific meetings and at lab rotations and several soft skill seminars.

As a major achievement, the CAVNET consortium succeeded to generate mouse models that enable the selective analysis of Cav1.3 and Cav1.2 channels. This was possible through improved analysis of existing and generation of new mice models, the latter enabling a selective ablation of channel isoforms in distinct organs. The joint usage of animal models required a strong interactive network activity, including shipping of animals and tissue, transfer of methodologies and lab rotations of fellows. This strongly cross-fertilised a positive atmosphere among fellows and network partners who developed amicable relationships while constantly improving technical skills and scientific knowledge to work on different organs.

Certainly, this positive atmosphere contributed to multiple new discoveries made in the CAVNET consortium, few of which will be highlighted here:
A preferential function of Cav1.3 channels could be manifested for initiating and maintaining pacemaker activity or spontaneous spike activity in the heart, adrenal gland or hair cells linked to defined structural characteristics. A new human genetic disease leading to heart disease and deafness could be linked to dysfunction of Cav1.3.
An entirely new expression pattern of Cav1.3 in the brain suggested so far undiscovered roles of this channel for neurogenesis or stem cell proliferation.
The CAVNET consortium could underscore the importance of normal membrane surface expression of Ca-channels for inner ear or pancreas function showing that deletion or disturbance of proteins that typically control the surface expression lead to hearing dysfunction and diabetes-like pathology.
The CAVNET consortium moreover discovered novel functions of Cav1.2 in the cochlea and of Cav1.3 in defined brainstem neurons likely linked to sound processing and localisation.
Finally, differential functions of both Cav1.2 and Cav1.3 in the adrenal gland were discovered, regulated by divergently acting signalling cascades that obviously tightly control the opening of these channels and thereby our fight- or flight body reaction.

It should be emphasised that through on-going analyses of mouse models, the majority of the CAVNET consortium remains connected beyond the duration of the funding period. The high-demanding, interdisciplinary training, the stimulating international environment, the existing or upcoming author- or co-authorships also in high-ranking journals fostered self-confidence and self-development of the fellows tremendously. The training network CAVNET successfully enhanced the career prospects of the young researchers resulting in many of the former fellows now having taken up positions in renowned laboratories.