Brian K. Kobilka
Title
Professor
Department
Molecular and Cellular Physiology and Medicine
Research Interests
G protein coupled receptors
Email
kobilka@stanford.edu
Phone
723-7069
Fax
498-5092
Address
Beckman B157
Mail Code: 5345
Faculty Research Description
Research in my lab is directed at understanding the structural basis for
the functional properties of G protein coupled receptors (GPCRs). GPCRs
are natureÕs most versatile biological sensors. They conduct the majority
of transmembrane responses to hormones and neurotransmitters, and mediate
the senses of sight, smell and taste. Adrenergic receptors, which transmit
signals from sympathetic nerves to the cardiovascular system, are one
of the most extensively characterized subfamilies of GPCRs, and serve
as a model system for understanding the structure, cell biology, and physiology
of GPCRs. We are investigating adrenergic receptors using a broad spectrum
of approaches. These range from using biochemical and biophysical tools
to elucidate ligand-induced conformational changes, to using in vitro
and in vivo systems to determine the structural basis for more complex
functional properties that are only observed in differentiated cells.
My group has developed direct methods to monitor ligand-induced conformational changes in purified, beta 2 adrenergic receptor, and we are attempting to obtain a high-resolution structure of this receptor. Our results suggest that agonists bind in a stepwise process in which some receptor-ligand interactions form rapidly, while other interactions cannot form until stochastic conformational fluctuations make the complete binding pocket accessible. Our data argue for a multi-state model of receptor activation, with different agonists inducing distinct active states.
We have also developed strains of knockout mice for five adrenergic receptor subtypes. These mice have provided insight into the physiologic role of specific receptor subtypes in vivo. We found that beta 1 and beta 2 adrenergic receptors play unique roles in regulating cardiovascular function. We are using neonatal myocytes from beta1/beta2 adrenergic receptor double knockout mice as a differentiated expression system to study the structural basis for differences in the functional properties of these two receptors.
Gether, U., Lin, S., Ghanouni, P., Ballesteros, J.A., Weinstein, H., and Kobilka, B.K. Agonists induce conformational changes in transmembrane domains III and VI of the beta2 adrenoceptor. Embo J, 1997. 16(22): p. 6737-47.
Chruscinski, A.J., Rohrer, D.K., Schauble, E., Desai, K.H., Bernstein, D., and Kobilka, B.K. Targeted disruption of the b2 adrenergic receptor gene. J Biol Chem, 1999. 274(24): p. 16694-700.
Rohrer, D.K., Chruscinski, A., Schauble, E.H., Bernstein, D., and Kobilka, B.K. Cardiovascular and metabolic alterations in mice lacking both b1- and b2-adrenergic receptors. J Biol Chem, 1999. 274(24): p. 16701-8.
Hein, L., Altman, J.D., and Kobilka, B.K. Two functionally distinct alpha2-adrenergic receptors regulate sympathetic neurotransmission. Nature, 1999. 402(6758): p. 181-4.
Ghanouni, P., Steenhuis, J.J., Farrens, D.L., and Kobilka, B.K., Agonist-induced conformational changes in the G protein coupling domain of the beta 2 adrenergic receptor. Proc Natl Acad Sci U S A, 2001. 98(11):p.5997-6002.
Ghanouni, P., Gryczynski, Z., Steenhuis, J.J., Lee, T.W., Farrens, D.L., Lakowicz, J.R., and Kobilka, B.K., Functionally different agonists induce distinct conformations in the G protein coupling domain of the beta 2 adrenergic receptor. J Biol Chem, 2001. 276(27):p. 24433-6.
Areas of Study
Cellular Neurobiology
Molecular Neurobiology
SBRC
Ph.D.